2-sulfamoylbenzoic acid derivatives

ABSTRACT

2-Sulfamoylbenzoic acid derivatives of general formula (I):                    
     which have both an antagonistic effect on the leukotriene D 4  receptor and an antagonistic effect on the thromboxane A 2  receptor and salts thereof, pharmaceuticals, anti-allergic agents and leukotrienethromboxane A 2  antagonistic agents containing them as an active ingredient.

DESCRIPTION

This application is a 371 of PCT/JP98/02585 filed Jun. 12, 1998.

TECHNICAL FIELD

The present invention relates to novel 2-sulfamoylbenzoic acidderivatives which have an antagonistic effect on both the leukotriene D₄(hereinafter referred to simply as LTD₄) receptor and the thromboxane A₂(hereinafter referred to simply as TXA₂) receptor, intermediates fortheir synthesis and their salts and medicines containing them.

BACKGROUND ART

For treatment of allergic diseases including bronchial asthma,anti-allergic agents such as histamine receptor antagonists and mediatorrelease suppressants for mast cells and steroid drugs have been used,and for bronchial asthma, bronchodilators such as xanthine derivativesand stimulators for the β-sympathetic nerve receptor have been used aswell.

In recent years, allergic diseases are recognized as allergicinflammations by their pathological profiles and have been found to beassociated with various inflammatory cells and mediators. For example,bronchial asthma is characterized by increased sensitivity of therespiratory tract to various stimuli and defined as involving reversiblestenosis of the respiratory tract, mucosal edema of the respiratorytract, mucous supersecretion and infiltration of inflammatory cells ontothe walls of the respiratory tract.

Further, with respect to the related mediators, it is suggested thatLTD₄ not only has an intense bronchoconstrictor effect but also enhancesthe permeability of the respiratory tract vessels and mucus secretion,and that TXA₂ not only has a potent bronchoconstrictor effect but alsocontrols the sensitivity of the respiratory tract.

With the above-mentioned movements in research on treatment of allergicdiseases, LTD₄ receptor antagonists, TXA₂ synthesis inhibitors and TXA₂receptor antagonists have been marketed and shown to be more effectivethan conventional anti-allergic agents.

However, because development of allergic diseases represented bybronchial asthma pathologically involves various mediators in parallelas mentioned above, antagonism against a receptor for a single mediatoror inhibition of synthesis of a single mediator has its limit in termsof effect, and development of novel promising anti-allergic agents whichshow greater therapeutic effects by inhibiting both LTD₄ and TXA₂, majorpathological mediators in allergy.

Compounds which have antagonistic effects on the receptors for both ofthe two mediators, LTD₄ and TXA₂, are disclosed in JP-A-3-258759,JP-A-4-154757, JP-A-4-154766, JP-A-5-262736, JP-A-5-279336, JP-A-6-41051and WO96/11916. These compound are structurally different from thecompounds of the present invention and are not expected to havesatisfactory therapeutic effects as anti-allergic agents in view of theintensities of their antagonistic effects on the receptors for the majorbronchoconstricting mediator LTD₄ and the ratios of their antagonisticactivities against the two mediators LTD₄ and TXA₂.

The present invention has been accomplished in view of the currentsituations in treatment of allergic diseases and research on theirtreatment with the aim of providing novel compounds which show potentantagonistic effects on the receptors for LTD₄ and TXA₂, which are thetwo major mediators in development of allergic diseases, and thereforeare expected to have more excellent therapeutic effects andpharmaceuticals containing them as active ingredients.

DISCLOSURE OF THE INVENTION

In the above-mentioned movements in treatment of allergic diseases andresearch on their treatment, the present inventors have conductedextensive research with a view to attaining the above-mentioned objectand, as a result, found out that the 2-sulfamoylbenzoic acid derivativesof the present invention have antagonistic effects on the receptors forthe two mediators LTD₄ and TXA₂, which play important roles indevelopment of allergic diseases, and have more excellent therapeuticeffects than the above-mentioned receptor antagonists against a singlemediator and inhibitors against synthesis of a single mediator. Thepresent inventors have accomplished the present invention on the basisof this discovery.

Namely, the present invention provides 2-sulfamoylbenzoic acidderivatives represented by general formula (I):

(wherein R1 and R2 which may be the same or different, are hydrogenatoms, C₃₋₈ cycloalkyl groups, optionally substituted C₁₋₆ alkyl groups,optionally substituted aryl groups or form, together with the ring

a condensed ring represented by formula

which may be substituted with an optionally substituted C₁₋₆ alkylgroup, an amino group, a cyano group, a nitro group, a hydroxyl group, ahalogen atom or a C₁₋₅ alkoxy group, X is an oxygen atom, a nitrogenatom, a sulfur atom or —CH═CH—, R3 is an optionally substitutedphenylsulfonylamino group, an optionally substituted phenylsulfonylgroup or an optionally substituted phenylsulfoxide group, R4 is ahydrogen atom or an ester residue, n is an integer of from 2 to 6, A is—O—B—, —B—O—, —S—B—, —B—S— or —B—, and B is a C₁₋₆ alkylene group or aC₂₋₅ alkenylene group, provided that the cases wherein R1 is a C₁₋₆alkyl group, a C₃₋₈ cycloalkyl group or a phenyl group, R2 is a hydrogenatom, A is a vinylene group, and X is a sulfur atom are excluded) orsalts, hydrates or solvates thereof.

The present invention also provides, as useful intermediates for theirsynthesis, benzylamine derivatives represented by general formula (II):

(wherein R1 and R2 which may be the same or different, are hydrogenatoms, C₃₋₈ cycloalkyl groups, optionally substituted C₁₋₆ alkyl groups,optionally substituted aryl groups or form, together with the ring

a condensed ring represented by formula

which may be substituted with an optionally substituted C₁₋₆ alkylgroup, an amino group, a cyano group, a nitro group, a hydroxyl group, ahalogen atom or a C₁₋₅ alkoxy group, X is an oxygen atom, a nitrogenatom, a sulfur atom or —CH═CH—, R3 is an optionally substitutedphenylsulfonylamino group, an optionally substituted phenylsulfonylgroup or an optionally substituted phenylsulfoxide group, n is aninteger of from 2 to 6, A is —O—B—, —B—O—, —S—B—, —B—S— or —B—, and B isa C₁₋₆ alkylene group or a C₂₋₅ alkenylene group, provided that thecases wherein R1 is a C₁₋₆ alkyl group, a C₃₋₈ cycloalkyl group or aphenyl group, R2 is a hydrogen atom, A is a vinylene group, and X is asulfur atom are excluded) or salts thereof, benzaldehyde derivativesrepresented by general formula (IIIa):

(wherein R1 and R2 which may be the same or different, are hydrogenatoms, C₃₋₈ cycloalkyl groups, optionally substituted C₁₋₆ alkyl groups,optionally substituted aryl groups or form, together with the ring

a condensed ring represented by formula

which may be substituted with an optionally substituted C₁₋₆ alkylgroup, an amino group, a cyano group, a nitro group, a hydroxyl group, ahalogen atom or a C₁₋₅ alkoxy group, A′ is —B′—O— or —B′—, and B′ is aC₁₋₆ alkylene group) or salts thereof, benzonitrile derivativesrepresented by general formula (IV):

(wherein RI and R2 which may be the same or different, are hydrogenatoms, C₃₋₈ cycloalkyl groups, optionally substituted C₁₋₆ alkyl groups,optionally substituted aryl groups or form, together with the ring

a condensed ring represented by formula

which may be substituted with an optionally substituted C_(l-6) alkylgroup, an amino group, a cyano group, a nitro group, a hydroxyl group, ahalogen atom or a C₁₋₅ alkoxy group, and X is an oxygen atom, a nitrogenatom, a sulfur atom or —CH═CH—)or salts thereof and amine derivativesrepresented by general formula (V):

H₂N—(CH₂)_(n)—R₃

(wherein n is an integer of from 2 to 6, and R3 is an optionallysubstituted phenylsulfonylamino group, an optionally substitutedphenylsulfonyl group or an optionally substituted phenylsulfoxide group)or salts thereof. The present invention further provides apharmaceutical, anti-allergic agent and leukotriene and thromboxane A₂antagonistic agent containing a 2-sulfamoylbenzoic acid derivativerepresented by general formula (I) or a salt, hydrate or solvate thereofas an active ingredient.

In general formulae (I), (II), (IIIa), (IV) and (V) mentioned above, a“C₃₋₈ cycloalkyl group” is a cyclopropyl group, a cyclobutyl group, acyclopentyl group, a cyclohexyl group, a cycloheptyl group or acyclooctyl group, preferably a cyclopropyl group or a cyclobutyl group.

A “C₁₋₆ alkyl group” is a linear or branched alkyl group such as amethyl group, an ethyl group, a propyl group, an isopropyl group, an-butyl group, an isobutyl group, a tert-butyl group, a n-pentyl groupor a n-hexyl group, preferably an isopropyl group or a tert-butyl group.

An “optionally substituted aryl group” is a carbocyclic aryl group suchas a phenyl group or a naphthyl group, which may have, as a substituent,a halogen atom such as a fluorine atom, a chlorine atom, a bromine atomor an iodine atom, a C₁₋₆ alkyl group such as a methyl group or an ethylgroup or a C₁₋₅ alkoxy group such as a methoxy group or an ethoxy group,preferably a fluorine atom, a chlorine atom, a bromine atom, a methylgroup or a methoxy group.

A “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom oran iodine atom.

A “C₁₋₅ alkoxy group” is a methoxy group, an ethoxy group, a n-propoxygroup, a n-butoxy group, an isobutoxy group, a tert-butoxy group or an-pentoxy group, preferably a methoxy group or an ethoxy group.

An “optionally substituted phenylsulfonylamino group”, an “optionallysubstituted phenylsulfonyl group” and an “optionally substitutedphenylsulfoxide group” may have, as a substituent, a halogen atom suchas a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, aC₁₋₆ alkyl group such as a methyl group or an ethyl group or a C₁₋₅alkoxy group such as a methoxy group or an ethoxy group, preferably afluorine atom, a chlorine atom, a bromine atom, a methyl group or amethoxy group, at the ortho-position, meta-position, or para-position,preferably at the para-position.

An “ester residue” is an ester residue such as a C₁₋₆ alkyl group, abenzyl group, a phenethyl group or a 1-naphthyl group or an ester groupmetabolically hydrolysable in vivo such as a lower alkanoyloxy loweralkyl group like an acetyloxymethyl group, a lower alkenoyl lower alkylgroup like a vinylcarbonylmethyl group, a cycloalkylcabonyloxy loweralkyl group like a cyclopropylcarbonyloxymethyl group, a loweralkenoyloxy lower alkyl group like a vinylcaronyloxymethyl group, alower alkoxy lower alkyl group like a methoxymethyl group, a loweralkoxy lower alkoxy lower alkyl group like a methoxymethoxymethyl group,a lower alkoxycarbonyloxy lower alkyl group like amethoxycarbonyloxymethylmethyl group, a benzoyloxy lower alkyl grouplike a benzoyloxymethyl group, a 2-oxotetrahydrofuan-5-yl group or a2-oxo-5-(lower alkyl)-1,3-dioxolen-4-ylmethyl group. Herein, “lower”means a linear or branched carbon chain having a carbon number of 1 to6.

A “C₁₋₆ alkylene group” is a linear or branched alkylene group such as amethylene group, an ethylene group, a methylmethylene group, atrimethylene group, a propylene group, a dimethylmethylene group, atetramethylene group, a 1-methyltrimethylene group, a2-methyltrimethylene group, a 3-methyltrimethylene group, a1-ethylethylene group, a 2-ethylethylene group, 2,2-dimethylethylene,1,1-dimethylethylene, an ethylmethylmethylene group, a pentamethylenegroup, 1-methyltetramethylene, 2-methyltetramethylene, a3-methyltetramethylene group, a 4-methyltetramethylene group, a1,1-dimethyltrimethylene group, a 2,2-dimethyltrimethylene group, a3,3-dimethyltrimethylene group, a 1,3-dimethyltrimethylene group, a2,3-dimethyltrimethylene group, 1,2-dimethyltrimethylene, a1,1,2-trimethylethylene group, a diethylmethylene group, a hexamethylenegroup, a 1-methylpentamethylene group, a 1,1-dimethyltetramethylenegroup or a 2,2-dimethyltetramethylene group, preferably a methylenegroup, an ethylene group, a propylene group, a methylmethylene group ora dimethylmethylene group.

A “C₂₋₅ alkenylene group” is a vinylene group, a propenylene group or abutenylene group, preferably a vinylene group.

The present invention covers the racemic bodies, diastereomers and anyoptical isomers of compounds of the present invention represented bygeneral formulae (I), (II), (IIIa), (IV) and (V) which have one or moreasymmetric carbon atom. Further, the present invention also covers anygeometrical isomers of the compounds of the present invention inclusiveof the (E)-forms, (Z)-forms and mixtures thereof.

The pharmaceutically acceptable salts useful in the formulae (I), (II),(IIIa), (IV) and (V) of the invention include inorganic salts suchhydrohalides such as hydrofluorides, hydrochlorides, hydrobromides andhydroiodides, nitrates, perchlorates, sulfates, phosphates andcarbonates, lower alkylsulfonates such as methanesulfonates,trifluoromethanesulfonates and ethanesulfonates, arylsulfonates such asbenzenesulfonates and p-toluenesulfonates, carboxylates such asacetates, fumarates, succinate, citrates, tartrates, oxalates andmaleates, amino acid salts such as glycine salts, alanine salts,glutamates and aspartates and alkali metal salts such as sodium saltsand potassium salts. The pharmaceutically acceptable solutions which canform a solvate with the compound according to the present inventioninclude solvates with acetone, 2-butanol, 2-propanol, ethanol, ethylacetate, tetrahydrofuran and diethyl ether.

The compounds of the present invention represented by general formulae(I), (II), (IIIa), (IV) and (V) can be produced by the processesdescribed below.

[Process A] Process for producing the compounds of the present inventionrepresented by general formulae (I) and (II)

(wherein R1, R2, X, R3, n and A are the same as defined above, and R4ais an ester residue.)

The first step is conventional reductive amination of an aldehyderepresented by general formula (III) with an amine represented bygeneral formula (V) and yields a benzylamine derivative represented bygeneral formula (II).

This step is usually accomplished by in situ formation of anintermediary imine represented by general formula (II′) from thealdehyde represented by general formula (III) and the amine representedby general formula (V) followed by reduction with an appropriatereducing agent. For formation of the intermediary imine, as the reactionsolvent, methanol, ethanol, isopropanol, benzene or toluene ispreferable, though there is no particular restriction unless thereaction is considerably inhibited. The reaction temperature ispreferably from 20° C. to 140° C., and the reaction time is preferablyfrom 1 to 24 hours. For reduction of the intermediary imine, as thereducing agent, for example, isodium borohydride or lithium aluminumhydride is preferable, though any usual reducing agent that can reducean imino group to an amino group can be used without any particularrestriction. With respect to the amounts of the respective reactants,the compound of general formula (V) is used preferably in an amount of 1to 5 equivalents based on the compound of general formula (III), and thereducing agent is used preferably in an amount of from 1 to 5equivalents based on the compound of general formula (III). The reactionsolvent is preferably methanol, ethanol or isopropanol though there isno particular restriction unless the reaction is considerably inhibited.The reaction temperature is preferably from 0° C. to 70° C., and thereaction time is preferably from 30 minutes to 12 hours.

The second step is conventional sulfonamidation of the benzylaminederivative (II) obtained in the first step with a2-chlorosulfonylbenzoic acid ester in the presence of a base and yieldsa 2-sulfamoylbenzoic acid derivative (Ia) which has an ester residue asR4 in general formula (I). The base may be either an aliphatic amine oran aromatic amine, preferably triethylamine or pyridine. With respect tothe amounts of the respective reactants, the 2-chlorosulfonylbenzoicacid ester is used preferably in an amount of 1 to 3 equivalents basedon the benzylamine derivative (II), and the base is used preferably inan amount of from 1 to 5 equivalents based on the benzylamine derivative(II). The reaction solvent is preferably chloroform, dichloromethane,1,2-dichloroethane or 1,1,2,2-tetrachloroethane, though there is noparticular restriction unless the reaction is considerably inhibited.The reaction temperature is preferably from 0° C. to 100° C., and thereaction time is preferably from 30 minutes to 12 hours.

The third step is conventional hydrolysis of the compound of generalformula (Ia) obtained in the second step and yields a compound of thepresent invention, wherein R4 is a hydrogen atom, represented by generalformula (Ib). For this reaction, conventional hydrolysis in the presenceof a base may be employed. The base is preferably a metal hydroxide ormetal carbonate such as sodium hydroxide, potassium hydroxide, sodiumcarbonate or potassium carbonate. With respect to the amounts of therespective reactants, the base is used preferably in an amount of 1 to50 equivalents based on the ester compound (Ia). The reaction solvent ispreferably water, methanol, ethanol, tetrahydrofuran or a mixturethereof though there is no particular restriction unless the reaction isconsiderably inhibited. The reaction temperature is preferably from 0°C. to 100° C., and the reaction time is preferably from 30 minutes to 24hours.

A compound (Ia) of the present invention is also obtainable byesterification of a compound (Ib) of the present invention whichcomprises conversion of the compound (Ib) of the present invention intoan acid halide with a halogenating agent such as thionyl chloride,oxalyl chloride or thionyl bromide followed by treatment with an alcoholin the presence or absence of a base. For formation of the acid halide,as the reaction solvent, dichloromethane, chloroform,1,2-dichloroethane, 1,1,2,2-tetrachloroethane or toluene is preferable,though there is no particular restriction unless the reaction isconsiderably inhibited. The reaction temperature is preferably from 0°C. to 100° C., and the reaction time is preferably from 1 to 12 hours.

The base used for the esterification may be either an aliphatic amine oran aromatic amine, preferably triethylamine or pyridine. With respect tothe amounts of the respective reactants, the alcohol is used preferablyin an amount of from 1 to 10 equivalents based on the acid halide, andthe base is used preferably in an amount of from 1 to 5 equivalentsbased on the acid halide. The reaction solvent may be dichloromethane,chloroform, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, toluene orthe alcohol used for the esterification, though there is no particularrestriction unless the reaction is considerably inhibited. The reactiontemperature is preferably from 0° C. to 80° C., and the reaction time ispreferably from 30 minutes to 12 hours.

A compound (Ia) of the present invention is also obtainable from acompound (Ib) of the present invention through reaction with an alcoholusing a condensing agent such as dicyclohexylcarbodiimide,1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide or1,1′-carbonyldiimidazol. The condensing agent is used preferably in anamount of from 1 to 2 equivalents based on the compound (Ib) of thepresent invention. The reaction solvent is preferablyN,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, dioxane,dichloromethane, chloroform or 1,2-dichloroethane though there is noparticular restriction unless the reaction is considerably inhibited.The reaction temperature is preferably from 0° C. to 70° C., and thereaction time is preferably from 1 to 48 hours. In the cases of sometypes of reaction solvents, more than one equivalent ofN-hydroxysuccinimide or N-hydroxybenzotriazole may be added beforehandso that the reaction proceeds smoothly.

[Process B] Process for producing the compounds (IIIb) of generalformula (III) wherein X is a sulfur atom, and A is —CH₂O—

(wherein R1 and R2 are the same as defined above except that they do notform a condensed ring, and Hal is a bromine atom or a chlorine atom.)

Firstly, a compound represented by formula (a) reacts with a compound(b) in the presence of a base to give a compound (c). The base used forthe reaction is preferably a metal carbonate such as potassium carbonateor sodium carbonate or a metal hydride such as sodium hydride orpotassium hydride. As the reaction solvent, N,N-dimethylformamide,dimethyl sulfoxide or acetone may be mentioned, though there is noparticular restriction unless the reaction is considerably inhibited.The reaction temperature is preferably from 0° C. to 100° C., and thereaction time is preferably from 30 minutes to 8 hours. Then, theresulting compound (c) reacts with O,O-diethyl dithiophosphate (d) togive a compound (e). For the reaction, O,O-diethyl dithiophosphate isused preferably in an amount of from 1 to 5 equivalents based on thecompound (c). The reaction solvent is preferably water or a solventmixture of an organic solvent/water, though there is no particularrestriction unless the reaction is considerably inhibited, and as theorganic solvent, dimethoxyethane, tetrahydrofuran or acetone ispreferable. The reaction temperature is preferably from 25° C. to 100°C., and the reaction time is preferably from 30 minutes to 8 hours. Theresulting compound (e) reacts with a bromoketone represented by formula(f) to give a compound represented by general formula (IIIb). Withrespect to the amounts of the respective reactants, the bromoketonerepresented by formula (f) is used preferably in an amount of from 1 to2 equivalents based on the compound (e). The reaction solvent ispreferably a lower alcohol such as methanol, ethanol or isopropanolthough there is no particular restriction unless the reaction isconsiderably inhibited. The reaction temperature is preferably from 25°C. to 100° C., and the reaction time is preferably from 30 minutes to 24hours.

[Process C] Process for producing the compounds (IIIc) of generalformula (III) wherein A is —CH₂O—

(wherein R1, R2, X and Hal are the same as defined above.)

A compound represented by formula (g) and a compound (b) undergoalkylation in the presence of a base to give a compound represented bygeneral formula (IIIc). As the base used for the reaction, a metalcarbonate such as potassium carbonate or sodium carbonate or a metalhydroxide such as sodium hydride or potassium hydride is ipreferable,and the base is used preferably in an amount of from 1 to 10 equivalentsbased on the compound (b). As the reaction solvent,N,N-dimethylformamide, dimethyl sulfoxide or acetone may be mentioned,though there is no particular restriction unless the reaction isconsiderably inhibited. The reaction temperature is preferably from 30°C. to 100° C., and the reaction time is preferably from 30 minutes to 8hours.

[Process D] Process for producing the compounds (IIId) of generalformula (III) wherein A is an ethylene group and the compounds of thepresent invention represented by general formula (IV)

(wherein R1, R2, X and Hal are the same as defined above.)

A compound represented by formula (h) reacts with a compound (i) in thepresence of a base to give a compound represented by formula (IV). Asthe base, an alkyl metal salt such as n-butyllithium, tert-butyllithium,lithium disiopropylamide or potassium tert-butoxide is preferably used.The base is used preferably in an amount of from 1 to 5 equivalentsbased on the compound of formula (h). As the reaction solvent,tetrahydrofuran, diethyl ether or toluene is preferable, though there isno particular restriction unless the reaction is considerably inhibited.The reaction temperature is preferably from −100° C. to 50° C., and thereaction time is preferably from 30 minutes to 12 hours. The subsequentreduction of the nitrile group in the resulting compound represented bygeneral formula (IV) with a reducing agent affords a compoundrepresented by general formula (IIId). The reducing agent is preferablya metal hydride, particularly diisopropylaluminum hydride, though anyreducing agent that can reduce a nitrile group into an aldehyde groupmay be used without any no particular restriction, and used in an amountof from 1 to 2 equivalents based on the compound of general formula(IV). As the reaction solvent, tetrahydrofuran, diethyl ether or toluenemay be mentioned, though there is no particular restriction unless thereaction is considerably inhibited. The reaction temperature ispreferably from −100° C. to 50° C., and the reaction time is preferablyfrom 30 minutes to 12 hours.

[Process E] Process for producing the compounds (IIId) of generalformula (III) wherein A is an ethylene group

(wherein R1, R2 and X are the same as defined above.)

Catalytic hydrogenation of a compound represented by general formula(IIIe) in the presence of a catalyst affords a compound represented bygeneral formula (IIId). As the hydrogenation catalyst, 5% palladiumcarbon, 10% palladium carbon, 30% palladium carbon, platinum oxide orWilkinson's catalyst is preferable. The catalyst is used preferably inan amount of from {fraction (1/10)} to 1 time the weight of the compound(IIIe), and the hydrogen pressure is preferably from 1 to 5 atm. As thereaction solvent, methanol, ethanol, ethyl acetate or tetrahydrofuran ispreferable, though there is no particular restriction unless thereaction is considerably inhibited. The reaction temperature ispreferably from 25° C. to 70° C., and the reaction time is preferablyfrom 1 to 72 hours.

[Process F] Process for producing the compounds (Va) of general formula(V) wherein R3 is an optionally substituted phenylsulfonyl group

(wherein n and Hal are the same as defined above, P is a protectinggroup, and Z is a hydrogen atom, a halogen atom, a C₁₋₆ alkyl group or aC₁₋₅ alkoxy group.)

An amino alcohol compound represented by formula (k) is converted into acompound of general formula (l) for protection of the amino group. Theprotection of the amino group can be accomplished by a conventionalmethod using a protecting group such as a phthalimido group, atert-butoxycarbonyl group or a benzyloxycarbonyl group. The resultingcompound of formula (l) is converted into a compound of formula (m) byreplacement of the hydroxyl group with a halogen atom. The halogenationcan be accomplished conventionally by bromination using phosphorustribromide or carbon tetrabromide/triphenylphosphine or chlorinationusing thionyl chloride or phosphorus pentachloride. The resultingcompound of formula (m) reacts with a thiophenol of formula (n) to givea compound of formula (o). The substitution can be accomplished by usinga base such as potassium carbonate or sodium hydride. The resultingcompound of formula (o) is oxidized to a compound represented by formula(p) and then finally converted into a compound of general formula (Va)through deprotection. For the oxidation, an oxidizing agent such asmetachloroperbenzoic acid may be used. For the deprotection,conventional methods may be used according to the protecting group.

[Process G] Process for producing the compounds (Vb) of general formula(V) wherein R3 is an optionally substituted phenylsulfonylamino group

(wherein n and Z are the same as defined above.)

A diamine compound represented by formula (q) reacts with aphenylsulfonyl chloride represented by formula (r) to give a compound ofgeneral formula (Vb). With respect to the amounts of the respectivereactants, the diamine compound (q) is used preferably in an amount offrom 1 to 20 equivalents based on the compound of formula (r). As thereaction solvent, chloroform, 1,2-dichloroethane, dichloromethane or1,1,2,2-tetrachloroethane may be mentioned, though there is noparticular restriction. The reaction temperature is preferably from 0°C. to 50° C., and the reaction time is preferably from 1 to 8 hours.

The compounds of the present invention and intermediates produced in theabove-mentioned processes can be isolated in the forms of freecompounds, salts, hydrates, solvates with various solvents such asethanol or polymorphic crystals. Pharmaceutically acceptable salts ofthe compounds of the present invention are obtainable by conventionalsalt-forming reactions. Isolation can be accomplished through chemicaltechniques such as fractional extraction, crystallization and varioustypes of fractional chromatography. Their optical isomers can beobtained as stereochemically pure isomers from appropriately selectedstarting materials or by racemic resolution of racemic compounds.

The 2-sulfamoylbenzoic acid derivatives of general formula (I) thusobtainable have an excellent anti-allergic effect by virtue of theirantagonistic effects on both the LTD₄ receptor and the TXA₂ receptor andshow excellent effects as preventive and therapeutic agents on allergicbronchial asthma, rhinitis and conjunctivitis, atopic dermatitis,gastroenteritis, colitis, vernal catarrh, nephritis and other allergicdiseases. They are also useful as preventive and therapeutic agents fordiseases associated with leukotrienes and TXA₂ and widely applicable forprevention and treatment of ischemic heart and brain diseases, anginapectoris, inflammatory peptic ulcer and hepatopathy.

The 2-sulfamoylbenzoic acid derivatives of the present invention can beused by themselves or by using known drug formulations in various dosageforms, for example, for oral pharmaceuticals such as tablets, capsules,granules, fine granules, powders, liquids and syrups and for parenteralpharmaceuticals such as injections, nasal drops, eye drops, infusions,ointments, suppositories, inhalants, percutaneous pharmaceuticals andpatches.

The dosages of the medicines of the present invention depend on thecondition, age and body weight of the patient, the therapeutic effectand the mode and term of administration, but in the case of oraladministration to an adult, they are usually administered in an amountof from 0.1 mg to 10 g per day.

BEST MODE FOR CARRYING OUT THE INVENTION EXAMPLES

Now, the compounds of the present invention and their preparations willbe described in further detail with reference to Examples. However, thepresent invention should not be restricted to these specific Examples.The H¹-NMR spectra were obtained by means of a spectrometer, modelJNM-EX270 (270 MHz, JEOL Ltd.) by using tetramethylsilane (TMS) as aninternal standard, and the δ values were given in ppm. The DI-EI massspectra were obtained by means of a spectrometer, model QP1000EX(Shimadzu Corporation). The FAB mass spectra were obtained by means of ahigh resolution mass spectrometer, model JMN-HX110A (JEOL Ltd.).

Example 1 Preparation of3-[(4-isopropyl-2-thiazolyl)methoxy]benzaldehyde

50 g (0.41 mol) of m-hydroxybenzaldehyde and 49 g (0.41 mol) ofbromoacetonitrile were dissolved in 300 ml of N,N-dimethylformamide andstirred together with 85g (0.62 mol) of potassium carbonate and 6.0 g(0.04 mol) of sodium iodide at room temperature for 1.5 hours. Thesolvent was distilled off in vacuo, and then water and ethyl acetatewere added for extraction. The ethyl acetate layer was washed withsaturated aqueous sodium chloride and dried over magnesium sulfate andevaporated in vacuo for removal of the solvent. The residue was purifiedby silica gel column chromatography (eluent; chloroform) to give 58 g of3-cyanomethoxybenzaldehyde in a yield of 88%.

¹H-NMR(CDCl₃):4.86(2H,s) 7.25-7.30(1H,m) 7.44-7.64(3H,m) 10.01(1H,s).

Then, 50 g (0.31 mol) of 3-cyanomethoxybenznaldehyde was dissolved in500 ml of 1,2-dimethoxyethane and stirred together with 5.6 ml (0.31mol) of water and 52 ml (0.31 mol) of O,O-diethyl dithiophosphate at 70°C. for 3 hours. The solvent was distilled off in vacuo, and the residuewas washed with ether and filtered off to give 31 g of3-(thiocarbamoylmethoxy)benzaldehyde in a yield of 51%.

Mass(m/z):195(M+) 160 121; ¹H-NMR(CDCl₃):4.94(2H,s) 7.20-7.29(1H,m)7.44-7.58(3H,m) 7.97(2H,br) 9.99(1H,s).

Then, 32.9 g (0.38 mol) of methyl isopropyl ketone was dissolved in 291ml of methanol and mixed with 2.9 ml of 25% HBr-AcOH under cooling withice. 18.7 ml (0.36 mol) of bromine was added dropwise under cooling withice, and the reaction solution was stirred for 2 hours. The reactionsolution was stirred together with water at room temperature for 30minutes and then together with 3-(thiocarbamoylmethoxy)benzaldehyde atroom temperature for 5.5 hours. Water and saturated sodium hydrogencarbonate were added to adjust the pH to 8.0, and the reaction solutionwas extracted with ethyl acetate. The ethyl acetate layer was washedwith saturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate and evaporated in vacuo for removal of the solvent, and theresidue was purified by silica gel column chromatography (eluent;n-hexane:ethyl acetate=20:1) to give 64.3 g of the title compound in ayield of 68%.

¹H-NMR(CDCl₃): 1.33(6H,d,J=6.9 Hz) 3.12(1H,) 5.40(2H,s) 6.92(1H,d,J=0.99Hz) 7.26-7.31(1H,m) 7.47-7.54(3H,m) 9.98(1H,s).

Similarly, the compounds of Example 2 and 3 were prepared.

Example 2 3-[(4-Cyclobutyl-2-thiazolyl)methoxy]benzaldehyde

Mass(m/z):273(M+) 254 152; ¹H-NMR(CDCl₃): 1.90-2.10(2H,m)2.20-2.43(4H,m) 3.68(1H,quint) 5.40(2H,s) 6.94(1H,s) 7.26-7.30(1H,m)7.47-7.54(3H,m) 9.98(1H,s).

Example 3 3-[(4-Cyclopropyl-2-thiazolyl)methoxy]benzaldehyde

¹H-NMR(CDCl₃): 0.86-1.00(4H,m) 2.06(1H,m) 5.35(2H,s) 6.87(1H,s)7.24-7.31(1Hm) 7.44-7.53(3H,m)9.98(1H,s).

Example 4 Preparation of3-[2-(4-cyclobutyl-2-thiazolyl)ethyl]benzonitrile

766 mg (5 mmol) of 4-cyclobutyl-2-methylthiazole was dissolved in 15 mlof anhydrous tetrahydrofuran and mixed with 561 mg (5 mmol) of potassiumtert-butoxide, and 3 ml (5 mmol) of n-butyllithium (1.68M hexanesolution) was added dropwise at −78° C. After 3 hours of stirring at thesame temperature, 1270 mg (6 mmol) of 3-bromomethylbenzonitrile in 3 mlanhydrous tetrahydrofuran was added dropwise, and the reaction solutionwas stirred for one hour and 40 minutes. After addition of saturatedaqueous ammonium chloride, the reaction solution was extracted withdiethyl ether twice, and the organic layer was washed with saturatedaqueous sodium chloride, dried over anhydrous magnesium sulfate andevaporated in vacuo for removal of the solvent. The residue was purifiedby silica gel column chromatography (eluent; n-hexane:ethyl acetate=4:1)to give 876 mg of the title compound as a yellow oily substance in ayield of 64%.

Mass(m/z): 268(M+); ¹H-NMR(CDCl₃): 1.84-2.11(2H,m) 2.15-2.42(4H,m)3.11-3.19(2H,m) 3.25-3.52(2H,m) 3.57-3.70(1H,m) 6.75(1H,s) 7.35-7.52(4H,m).

Example 5 Preparation of3-[2-(4-cyclobutyl-2-thiazolyl)ethyl]benzaldehyde

875 mg (3.3 mmol) of 3-[2-(4-cyclobutyl-2-thiazolyl)ethyl]benzonitrilewas dissolved in 20 ml of toluene, and 3.6 ml (3.60 mmol) of 1.01Mdiisobutylaluminum hydride (toluene solution) was added at −78° C. Thereaction solution was brought back to room temperature and stirred for 2hours. The reaction solution was mixed with saturated aqueous ammoniumchloride and 2N hydrochloric acid successively and stirred for 1 hour,and the organic layer was washed with saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride, dried over anhydrousmagnesium sulfate and evaporated in vacuo for removal of the solvent.The residue was purified by silica gel column chromatography (eluent;n-hexane:ethyl acetate=4:1) to give 792 mg of the title compound as acolorless oily substance in a yield of 89%.

Mass(m/z): 271(M+) 242; ¹H-NMR(CDCl₃): 1.84-2.42(6H,m) 3.20(2H,m)3.32(2H,m) 3.64(1H,quint) 6.74(1H,d)J=0.66 Hz) 7.47(2H,m) 7.73(2H,m)9.99(1H,s).

Example 6 Preparation of 3-[2-(2-quinolyl)ethyl]benzaldehyde

5.5 g (21.2 mmol) of 3-[2-(2-quinolyl)ethenyl]benzaldehyde was dissolvedin 500 ml and hydrogenated in the presence of 1.1 g of 10% palladiumcarbon at atmospheric pressure at room temperature for 10 hours understirring. The 10% palladium carbon was filtered out through celite, andthe filtrate was evaporated in vacuo. The residue was purified by silicagel column chromatography (eluent; n-hexane:ethyl acetate=9:1) to give2.8 g (10.7 mmol) of the title compound in a yield of 51%.

Mass(m/z): 261(M+) 156; ¹H-NMR(CDCl₃): 7.46-7.60(3H,m) 7.65-7.91(6H,m)8.05-8.17(3H,m) 10.07(1H,s)

Example 7 Preparation of 5-(4-chlorophenylsulfonyl)pentanamine

10 g (96.9 mmo)of 5-amino-l-pentanol was dissolved in 300 ml of tolueneand refluxed together with 17.2 g (116 mmol) of phthalic anhydride at120° C. for 24 hours. The solvent was distilled off in vacuo, and theresidue was purified by silica gel column chromatography (eluent;chloroform) to give 16.6 g of 5-phthalimido-1-pentanol in a yield of74%.

Mass(m/z): 233(M+) 203 160; ¹H-NMR(CDCl₃): 1.37-1.48(2H,m)1.58-1.78(4H,m) 3.62-3.73(4H,m) 7.68-7.74(2H,m) 7.81-7.87(2H,m).

Then, 16.2 g of 5-phthalimido-1-pentanol was dissolved in 350 ml ofdiethyl ether, and 4.3 ml of phosphorus tribromide was added dropwise at0° C. The reaction solution was stirred at room temperature for 9 hoursand neutralized with saturated aqueous sodium hydrogen carbonate, andthe organic layer was washed with saturated aqueous sodium chloride,dried over anhydrous magnesium sulfate and evaporated in vacuo forremoval of the solvent. The residue was purified by silica gel columnchromatography (eluent; n-hexane:ethyl acetate=9:1) to give 9.2 g of1-bromo-5-phthalimidopentane in a yield of 45%.

Mass(m/z): 296(M+) 216 160; ¹H-NMR(CDCl₃): 1.44-1.55(2H,m)1.63-1.77(2H,m) 1.86-2.00(2H,m) 3.37-3.42(2H,m) 3.67-3.73(2H,m)7.68-7.75(2H,m) 7.81-7.88(2H,m).

Then, 9.2 g (31 mmol) of 1-bromo-5-phthalimidopentane was dissolved in100 ml of N,N-dimethylformamide and stirred together with 8.6 g (62mmol) of potassium carbonate, 465 mg (3.1 mmol) of sodium iodide and 4.5g (31 mmol) of 4-chlorothiophenol at room temperature for 15 hours. Thesolvent was distilled off in vacuo, and water and ethyl acetate wereadded for extraction. The ethyl acetate layer was washed with saturatedaqueous sodium chloride, dried over anhydrous magnesium sulfate andevaporated in vacuo for removal of the solvent. The residue was washedwith hexane to give 9.6 g of 1-(4-chlorophenylthio)-5-phthalimidepentanein a yield of 86%.

Mass(m/z): 359(M+) 216 160; ¹H-NMR(CDCl₃): 1.47-1.51(2H,m)1.64-1.72(4H,m) 2.88(2H,t J=7.26 Hz) 3.68(2H,t J=7.26 Hz) 7.23(4H,s)7.71-7.23(2H,m) 7.82-7.86(2H,m).

Then, 9.4 g (26.1 mmol) of 1-(4-chlorophenylthio)-5-phthalimidopentanewas dissolved in 350 ml of 1,2-dichloroethane and stirred together with9.9 g (57.4 mmol) of metachloroperbenzoic acid at room temperature for18 hours. The reaction solution was washed with 5% sodium thiosulfate,3% sodium hydrogen carbonate and saturated aqueous sodium chloride,dried over anhydrous magnesium sulfate and evaporated in vasuo forremoval of the solvent to give 9.7 g of1-(4-chlorophenylsulfonyl)-5-phthalimidopentane in a yield of 95%.

Mass(m/z): 391(M+) 216 160; ¹H-NMR(CDCl₃): 1.37-1.48(2H,m)1.61-1.81(4H,m) 3.05-3.11(2H,m) 3.62-3.93(3H,m) 7.52-7.57(2H,m)7.69-7.75(2H,m) 7.80-7.86(2H,m).

Then, 4.0 g (10.2 mmol) of1-(4-chlorophenylsulfonyl)-5-phthalimidopentane was dissolved in 120 mlof dichloromethane and 20 ml of ethanol and stirred together with 6 mlof 80% hydrazine hydrate at room temperature for 36 hours. Theimpurities were filtered out, and the filtrate was evaporated in vacuoto give 3.2 g of the title compound.

Example 8 Preparation of 4-(4-chlorophenylsulfonylamino)butanamine

26.4 g (0.3 mol) of 1,4-diaminobutane was dissolved in 100 ml of1,2-dichloroethene and stirred together with 6.3 g (0.03 mmol) of4-chlorophenylsulfonyl chloride at room temperature for 4 hours. Afteraddition of chloroform, the reaction solution was filtered throughcelite, and the filtrate was washed with water three times and withsaturated aqueous sodium chloride successively, dried over anhydrousmagnesium sulfate and evaporated in vacuo for removal of the solvent togive 5.1 g of the title compound in a yield of 65%.

Example 9 Preparation ofN-[4-(4-chlorobenzenesulfonylamino)butyl]-3-[(4-isopropyl-2-thiazolyl)methoxy]benzylamine(Compound No.1a)

2.27 g (8.69 mmol) of 3-[(4-isopropyl-2-thiazolyl)methoxy]benzaldehydeand 2.27 g (8.69 mmol) of 4-(4-chlorophenylsulfonylamino)butanamine weredissolved in 150 ml of ethanol and refluxed together with 4.0 g ofmolecular sieves 3A for 16 hours. The molecular sieves 3A was filteredout, and the filtrate was stirred together with 873 mg of sodiumborohydride at room temperature for 3 hours. The reaction solution wasevaporated in vacuo for removal of ethanol as the solvent and mixed withwater and ethyl acetate for ethyl acetate extraction. The ethyl acetatelayer was washed with saturated aqueous sodium chloride, dried overanhydrous magnesium sulfate and evaporated in vacuo for removal of thesolvent. The residue was purified by silica gel column chromatography(eluent; chloroform to chloroform:methanol=98:2) to giveN-[4-(4-chlorobenzenesulfonylamino)butyl]-3-[(4-isopropyl-2-thiazolyl)methoxy]benzylamine(Compound No.1a).

Compouns Nos.2a to 90a were prepared similarly. The mass spectrum dataare shown in Table 1.

TABLE 1

Compound No.

A R3 n FAB-MS (m/z)  1a

—CH₂O—

4 508 (M⁺) 315 246  2a

—CH₂O—

4 504 (M⁺) 330 258  3a

—CH₂O—

4 566 (M⁺) 331 258  4a

—CH₂O—

4 516 (M⁺) 330 258  5a

—CH₂O—

4 500 (M⁺) 330 258  6a

—CH₂O—

4 486 (M⁺) 330 258  7a

—CH₂O—

3 506 (M⁺) 316 258  8a

—CH₂O—

2 492 (M⁺) 302 258  9a

—CH₂O—

2 536 (M⁺) 301 258 10a

—CH₂O—

2 476 (M⁺) 302 258 11a

—CH₂O—

2 458 (M⁺) 302 258 12a

—CH₂O—

5 534 (M⁺) 344 258 13a

—CH₂O—

4 520 (M⁺) 329 258 14a

—CH₂O—

4 492 (M⁺) 318 246 15a

—CH₂O—

4 552 (M⁺) 317 246 16a

—CH₂O—

4 504 (M⁺) 319 246 17a

—CH₂O—

4 488 (M⁺) 318 246 18a

—CH₂O—

4 474 (M⁺) 318 246 19a

—CH₂O—

4 542 (M⁺) 352 280 20a

—CH₂O—

4 506 (M⁺) 316 244 21a

—CH₂O—

4 490 (M⁺) 316 244 22a

—CH₂O—

4 552 (M⁺) 317 244 23a

—CH₂O—

4 472 (M⁺) 316 244 24a

—CH₂O—

4 486 (M⁺) 316 244 25a

—CH₂O—

4 502 (M⁺) 316 244 26a

—CH₂O—

3 492 (M⁺) 302 244 27a

—CH₂O—

2 478 (M⁺) 288 244 28a

—CH₂O—

2 462 (M⁺) 288 244 29a

—CH₂CH₂—

4 518 (M⁺) 328 256 30a

—CH₂CH₂—

4 562 (M⁺) 327 256 31a

—CH₂CH₂—

4 485 (M⁺) 329 256 32a

—CH₂CH₂—

4 499 (M⁺) 329 256 33a

—CH₂CH₂—

4 490 (M⁺) 316 244 34a

—CH₂CH₂—

4 487 (M⁺) 317 244 35a

4 490 (M⁺) 316 244 36a

4 550 (M⁺) 315 244 37a

4 502 (M⁺) 316 244 38a

4 486 (M⁺) 316 244 39a

4 472 (M⁺) 316 244 40a

3 492 (M⁺) 302 244 41a

2 479 (M⁺) 289 244 42a

2 524 (M⁺) 289 278 43a

2 462 (M⁺) 288 244 44a

2 444 (M⁺) 288 244 45a

4 540 (M⁺) 350 278 46a

4 519 (M⁺) 345 278 47a

4 586 (M⁺) 351 278 48a

4 536 (M⁺) 350 278 49a

4 520 (M⁺) 350 278 50a

4 506 (M⁺) 350 278 51a

3 526 (M⁺) 336 278 52a

2 512 (M⁺) 322 278 53a

—CH₂O—

4 494 (M⁺) 320 248 54a

—CH₂O—

4 555 (M⁺) 322 248 55a

—CH₂O—

4 506 (M⁺) 320 248 56a

—CH₂O—

4 490 (M⁺) 320 248 57a

—CH₂O—

4 476 (M⁺) 320 248 58a

—CH₂O—

3 490 (M⁺) 300 248 59a

—CH₂O—

2 482 (M⁺) 292 248 60a

—CH₂O—

2 466 (M⁺) 292 248 61a

—CH₂O—

2 526 (M⁺) 291 248 62a

—CH₂O—

2 449 (M⁺) 293 248 63a

—CH₂O—

5 537 (M⁺) 347 248 64a

—CH₂O—

2 516 (M⁺) 326 282 65a

—CH₂O—

4 546 (M⁺) 356 282 66a

—CH₂CH₂—

4 508 (M⁺) 318 246 67a

—CH₂CH₂—

4 492 (M⁺) 318 246 68a

—CH₂CH₂—

4 488 (M⁺) 318 246 69a

—CH₂CH₂—

4 504 (M⁺) 318 246 70a

—CH₂CH₂—

4 554 (M⁺) 319 246 71a

—CH₂CH₂—

2 480 (M⁺) 290 246 72a

—CH₂CH₂—

3 494 (M⁺) 304 246 73a

—CH₂CH₂—

5 522 (M⁺) 332 246 74a

—CH₂CH₂—

4 542 (M⁺) 352 280 75a

—CH₂CH₂—

4 526 (M⁺) 352 280 76a

—CH₂CH₂—

4 522 (M⁺) 352 280 77a

—CH₂CH₂—

4 538 (M⁺) 353 280 78a

—CH₂CH₂—

4 588 (M⁺) 353 280 79a

—CH₂CH₂—

2 515 (M⁺) 325 280 80a

—CH₂CH₂—

3 528 (M⁺) 338 280 81a

—CH₂O—

5 519 (M⁺) 344 256 82a

—CH₂O—

5 505 (M⁺) 330 244 83a

—CH₂O—

5 507 (M⁺) 332 246 84a

5 505 (M⁺) 330 244 85a

5 539 (M⁺) 364 278 86a

—CH₂CH₂—

5 507 (M⁺) 332 280 87a

—CH₂CH₂—

5 541 (M⁺) 366 280 88a

—CH₂O—

5 509 (M⁺) 334 248 89a

—CH₂O—

4 510 (M⁺) 319 90a

4 506 (M⁺) 315

Example 10 Preparation of methyl[2-{N-[4-(4-chlorobenzenesulfonylamino)butyl]-N-{3-((4-isopropyl-2-thiazolyl)methoxy]benzyl}}sulfamoylbenzoate(Compound No.1b)

3.5 g (6.89 mmol) of the product in Example 9 (Compound 1a) wasdissolved in 150 ml of 1,2-dichloroethane and stirred together with 1.4ml (10.34 mmol) of triethylamine and 1.9 g (8.27 mmol) of methyl2-chlorosulfonylbenzoate at room temperature for 4 hours. The1,2-dichloroethane was distilled off in vacuo, and water and ethylacetate were added. The ethyl acetate was washed with saturated aqueoussodium chloride, dried over anhydrous magnesium sulfate and evaporatedin vacuo for removal of the solvent. The residue was purified by silicagel column chromatography (eluent; chloroform) to give 3.5 g (4.95 mmol)of2-{N-[4-(4-chlorobenzenesulfonylamino)butyl]-N-{3-[(4-isopropyl-2-thiazolyl)methoxy]benzyl}}sulfamoylbenzoate(Compound No.1b) in a yield of 72%.

Compounds Nos.2b to 90b were prepared similarly. The mass spectrum dataare shown in Table 2.

TABLE 2

(wherein R4 is a methyl group) Compound No.

A R3 n FAB-MS (m/z)  1b

—CH₂O—

4 706 (M⁺) 506  2b

—CH₂O—

4 702 (M⁺)  3b

—CH₂O—

4 764 (M⁺) 564  4b

—CH₂O—

4 714 (M⁺) 514  5b

—CH₂O—

4 698 (M⁺) 498  6b

—CH₂O—

4 684 (M⁺) 484  7b

—CH₂O—

3 704 (M⁺) 504  8b

—CH₂O—

2 690 (M⁺) 490  9b

—CH₂O—

2 734 (M⁺) 534 10b

—CH₂O—

2 674 (M⁺) 474 11b

—CH₂O—

2 656 (M⁺) 456 12b

—CH₂O—

5 732 (M⁺) 532 13b

—CH₂O—

4 718 (M⁺) 518 14b

—CH₂O—

4 690 (M⁺) 490 15b

—CH₂O—

4 750 (M⁺) 550 16b

—CH₂O—

4 702 (M⁺) 502 17b

—CH₂O—

4 686 (M⁺) 486 18b

—CH₂O—

4 672 (M⁺) 472 19b

—CH₂O—

4 740 (M⁺) 540 20b

—CH₂O—

4 704 (M⁺) 504 21b

—CH₂O—

4 684 (M⁺) 484 22b

—CH₂O—

4 750 (M⁺) 550 23b

—CH₂O—

4 670 (M⁺) 470 24b

—CH₂O—

4 684 (M⁺) 484 25b

—CH₂O—

4 700 (M⁺) 500 26b

—CH₂O—

3 690 (M⁺) 490 27b

—CH₂O—

2 676 (M⁺) 476 28b

—CH₂O—

2 660 (M⁺) 460 29b

—CH₂CH₂—

4 716 (M⁺) 516 30b

—CH₂CH₂—

4 760 (M⁺) 562 31b

—CH₂CH₂—

4 683 (M⁺) 483 32b

—CH₂CH₂—

4 697 (M⁺) 497 33b

—CH₂CH₂—

4 688 (M⁺) 488 34b

—CH₂CH₂—

4 685 (M⁺) 485 35b

4 688 (M⁺) 488 36b

4 748 (M⁺) 548 37b

4 700 (M⁺) 500 38b

4 684 (M⁺) 484 39b

4 670 (M⁺) 470 40b

3 690 (M⁺) 490 41b

2 677 (M⁺) 477 42b

2 722 (M⁺) 522 43b

2 660 (M⁺) 460 44b

2 642 (M⁺) 442 45b

4 738 (M⁺) 538 46b

4 717 (M⁺) 517 47b

4 784 (M⁺) 584 48b

4 734 (M⁺) 534 49b

4 718 (M⁺) 518 50b

4 704 (M⁺) 504 51b

3 724 (M⁺) 524 52b

2 710 (M⁺) 510 53b

—CH₂O—

4 692 (M⁺) 492 54b

—CH₂O—

4 753 (M⁺) 553 55b

—CH₂O—

4 704 (M⁺) 504 56b

—CH₂O—

4 688 (M⁺) 488 57b

—CH₂O—

4 674 (M⁺) 474 58b

—CH₂O—

3 688 (M⁺) 488 59b

—CH₂O—

2 680 (M⁺) 480 60b

—CH₂O—

2 664 (M⁺) 464 61b

—CH₂O—

2 724 (M⁺) 524 62b

—CH₂O—

2 657 (M⁺) 457 63b

—CH₂O—

5 735 (M⁺) 535 64b

—CH₂O—

2 714 (M⁺) 514 65b

—CH₂O—

4 744 (M⁺) 544 66b

—CH₂CH₂—

4 706 (M⁺) 506 67b

—CH₂CH₂—

4 690 (M⁺) 490 68b

—CH₂CH₂—

4 686 (M⁺) 486 69b

—CH₂CH₂—

4 702 (M⁺) 502 70b

—CH₂CH₂—

4 752 (M⁺) 552 71b

—CH₂CH₂—

2 678 (M⁺) 478 72b

—CH₂CH₂—

3 692 (M⁺) 492 73b

—CH₂CH₂—

5 720 (M⁺) 520 74b

—CH₂CH₂—

4 740 (M⁺) 540 75b

—CH₂CH₂—

4 724 (M⁺) 524 76b

—CH₂CH₂—

4 720 (M⁺) 520 77b

—CH₂CH₂—

4 736 (M⁺) 536 78b

—CH₂CH₂—

4 786 (M⁺) 586 79b

—CH₂CH₂—

2 713 (M⁺) 513 80b

—CH₂CH₂—

3 726 (M⁺) 526 81b

—CH₂O—

5 717 (M⁺) 517 82b

—CH₂O—

5 703 (M⁺) 503 83b

—CH₂O—

5 705 (M⁺) 505 84b

5 703 (M⁺) 503 85b

5 737 (M⁺) 537 86b

—CH₂CH₂—

5 705 (M⁺) 505 87b

—CH₂CH₂—

5 739 (M⁺) 539 88b

—CH₂O—

5 707 (M⁺) 507 89b

—CH₂O—

4 708 (M⁺) 509 90b

4 704 (M⁺) 505

Example 11 Preparation of2-{N-[4-(4-chlorobenzenesulfonylamino)butyl]-N-{3-[(4-isopropyl-2-thiazolyl)methoxy]benzyl}}sulfamoylbenzoicacid (Compound No.1)

3.2 g (4.53 mmol) of the product in Example 10 (Compound No.1b) wasdissolved in 70 ml of methanol and 70 ml of tetrahydrofuran and stirredtogether with 50 ml of 1N sodium hydroxide at 80° C. for 3 hours. Thereaction solution was evaporated in vacuo for removal of the solvent,mixed with water and neutralized with 1N hydrochloric acid, and thedeposited precipitate was filtered off to give 2.7 g (3.9 mmol) of thetitle compound (Compound No.1) in a yield of 86%.

Compounds Nos.2 to 90 were prepared similarly. The mass spectrum dataare shown in Table 3.

TABLE 3

Compound Compound No.

A R3 n Physicochemical properties 1

—CH₂O—

4 FAB-MS: (m/z)692(M⁺)508 458 246 ¹H NMR(CDCl₃) 1.31(10H, m)2.75(2H, brs)3.15(2H, t J=6.8Hz)4.40(2H, s)5.33(2H, s) 6.81-6.91(4H, m)7.15(1H, tJ=7.8Hz) 7.38(2H, d J=7.38Hz)7.51-7.64(3H, m) 7.71(2H, dJ=8.58Hz)7.90(1H, d J=7.26Hz) 2

—CH₂O—

4 FAB-MS: (m/z)688(M⁺)504 346 258 ¹H NMR(CDCl₃) 1.33(4H, m)1.88-2.12(2H,m)2.17-2.43 (4H, m)2.75(2H, br s)3.14(2H, br t)3.72(1H, quint)4.40(2H,s)5.12 (1H, br s)5.37(2H, s)6.81-6.90(2H, m) 6.95(1H, dJ=0.7Hz)7.08-7.14(3H, m)7.54-7.68(3H, m)7.80(2H, m)7.94 (1H, d J=7.59Hz)3

—CH₂O—

4 FAB-MS: (m/z)750(M⁺+1)670 564 ¹H NMR(CDCl₃) 1.26(4H, m)1.87-2.10(2H,m)2.06-2.40 (4H, m)2.71(2H, br s)3.13(2H, br s) 3.65(1H, quint)4.38 (2H,s)5.28(2H, s)5.68(1H, br s)6.83(2H, m)6.92 (1H, s)7.14(1H, tJ=7.9Hz)7.45-7.50 (5H, m)7.61(2H, d J=8.58Hz)7.82 (1H, d J=7.59Hz) 4

—CH₂O—

4 FAB-MS: (m/z)700(M⁺)516 365 240 ¹H NMR(CDCl₃) 1.26(4H, m)1.83-2.09(2H,m)2.1-2.36 (4H, m)3.11(2H, br s)3.67(1H, quint) 3.79(3H, s)4.35(2H, brs)5.26 (2H, br s)6.72-7.09(5H, m)7.12(1H, br s)7.26(1H, s)7.30-7.90(6H,m) 5

—CH₂O—

4 FAB-MS: (m/z)684(M⁺)645 500 ¹H NMR(CDCl₃) 1.22-1.32(4H,m)1.86-2.10(2H, m)2.16- 2.31(4H, m)2.36(3H, s)2.71(2H, br s) 3.13(2H, brs)3.72(1H, quint)4.38 (2H, 2)5.29(2H, s)6.81-6.92(4H, m) 7.10-7.21(3H,m)7.44-7.59(3H, m) 7.65(2H, d J=8.25Hz)7.87(1H, d J= 7.59Hz) 6

—CH₂O—

4 FAB-MS: (m/z)670(M⁺)486 346 ¹H NMR(CDCl₃) 1.23-1.34(4H,m)1.91-2.16(2H, m)2.19- 2.42(4H, m)2.73(2H, br s)3.13(2H, br s)3.71(1H,quint)4.39(2H, s) 5.11(1H, br s)5.34(2H, s)6.81-6.94 (4H, m)7.13(1H, tJ=7.76Hz)7.41-7.65 (6H, m)7.78(2H, d J=6.93Hz)7.92 (1H, d J=7.59Hz) 7

—CH₂O—

3 FAB-MS: (m/z)690(M⁺)346 258 ¹H NMR(CDCl₃) 1.41(2H, br s)1.92-2.12(2H,m)2.20- 2.42(4H, m)2.73(2H, br s)3.22(2H, br s)3.70(1H, quint)4.38(2H,s)5.33 (2H, s)5.74(1H, br s)6.80-6.94(4H, m)7.14(1H, t)7.35(2H, dJ=8.58Hz) 7.52-7.60(3H, m)7.69-(2H, d J=8.57Hz, 7.85(1H, d J=7.26Hz) 8

—CH₂O—

2 FAB-MS: (m/z)676(M⁺)492 458 ¹H NMR(CDCl₃) 1.92-2.40(6H, m)2.70(2H, brs)3.26 (2H, br s)3.71(1H, m)4.34(2H, s)5.40 (2H, s)6.19(1H, brs)6.77-6.97 (4H, m)7.12(1H, m)7.25-7.31(3H, m) 7.50-7.62(5H, m)7.93(1H,d) 9

—CH₂O—

2 FAB-MS: (m/z)720(M⁺)642 536 ¹H NMR(CDCl₃) 1.85-2.13(2H,m)2.15-2.44(4H, m)2.70 (2H br s)3.27(2H, t J=5.6Hz)4.34 (2H, s)5.42(2H,s)6.16(1H, br s) 6.77(1H, d J=7.91Hz)6.87-6.90(2H, m) 6.97(1H,s)7.42-7.63(7H, m)7.95(1H, d J=7.59Hz) 10

—CH₂O—

2 FAB-MS: (m/z)660(M⁺)476 258 ¹H NMR(CDCl₃) 1.85-2.43(4H, m)2.71(2H, brs)3.25 (2H, m)3.74(1H, quint)4.33(2H, s) 5.46(2H, s)5.97(1H, brs)6.77(1H, d J=7.58Hz)6.85-6.92(2H, m)6.98-7.15 (4H, m)7.54-7.69(5H,m)8.00(1H, d J=7.58Hz) 11

—CH₂O—

2 FAB-MS: (m/z)642(M⁺)458 ¹H NMR(CDCl₃) 1.89-2.43(6H, m)2.73(2H, brs)3.25 (2H, m)3.74(1H, quint)4.31(2H, s) 5.43(2H, s)5.89(1H, brs)6.77(1H, d J=7.58Hz)6.89(2H, m)6.97(1H, d J=0.66 Hz)7.11(1H, tJ=7.92Hz)7.35-7.70 70(3H, m)8.00(1H, d J=7.58Hz) 12

—CH₂O—

5 FAB-MS: (m/z)718(M⁺) 684 645 534 ¹H NMR(CDCl₃) 1.05(2H, m)1.27(4H,m)1.85-2.45(6H, m) 2.78(2H, m)3.10(2H, m)3.73(1H, quint) 4.40(2H,s)5.13(1H, br s)5.37 (2H, s)6.82-6.90(2H, m)6.95(2H, d J=0.66Hz)7.16(1H,m)7.46(2H, m)7.54- 7.74(3H, m)7.76(2H, dd J=1.98 6.93Hz) 7.96(1H, m) 13

—CH₂O—

4 FAB-MS: (m/z)704(M⁺)520 ¹H NMR(CDCl₃) 1.30(4H, m)1.90-2.08(2H,m)2.16-2.39 (4H, m)2.72(2H, br s)3.14(2H, br s) 3.71(1H, quint)4.40(2H,s)5.22(1H, br s) 5.36(2H, s)6.80-6.94(4H, m)7.13(1H, d J=7.59Hz)7.38(2H,d J=6.92Hz) 7.54-7.72(5H, m)7.89(1H, d) 14

—CH₂O—

4 FAB-MS: (m/z)676(M⁺)492 228 ¹H NMR(CDCl₃) 1.31(10H, m)2.77(2H,3.14(3H,m) 4.43(2H, s)5.14(1H, t J=5.78Hz)5.37 (2H, s)6.81-6.95(4H, m)7.08-7.18(3H, m)7.53-7.70(3H, m)7.81-7.92(2H, m) 7.94(1H, d J=7.59Hz) 15

—CH₂O—

4 FAB-MS: (m/z)736(M⁺)552 246 ¹H NMR(CDCl₃) 1.31(10H, m)2.74(2H,m)3.14(3H, m) 4.41(2H, s)5.35(2H, s)5.25(1H, br S) 6.81-6.92(4H,m)7.14(1H, t J=7.92Hz) 7.51-7.81(7H, m)7.90(1H, m) 16

—CH₂O—

4 FAB-MS: (m/z)688(M⁺)504 ¹H NMR(CDCl₃) 1.24-1.33(10H, m)2.73(2H,m)3.10- 3.23(3H, m)3.84(3H, s)4.39(2H, s)4.64 (1H, br s)4.92(1H, brs)5.36(2H, s) 6.82-6.94(6H, m)7.15(1H, t J=7.92Hz) 7.53-7.74(5H,m)7.95(1H, d J=7.59Hz) 17

—CH₂O—

4 FAB-MS: (m/z)672(M⁺)488 334 246 ¹H NMR(CDCl₃) 1.09-1.33(10H,m)2.39(3H, s)2.72(2H, m) 3.11-3.22(3H, m)4.40(1H, br s) 4.97(1H, brs)5.36(2H, s)5.59(1H, br s)6.82-6.93(4H, m)7.14(1H, t J=7.92Hz) 7.25(2H,d J=8.24Hz)7.7.52-7.68 (4H, m)7.94(1H, d J=7.26Hz) 18

—CH₂O—

4 FAB-MS: (m/z)658(M⁺)518 474 ¹H NMR(CDCl₃) 1.25-1.33(10H, m)2.76(2H,m)3.11-3.18 (3H, m)4.40(2H, s)5.13(1H, br s) 5.34(2H, s)6.82-6.93(4H,m)7.15(1H, t J=7.92Hz)7.43-7.67(6H, m)7.79(2H, d J=6.93Hz)7.93(1H, dJ=7.59Hz) 19

—CH₂O—

4 FAB-MS: (m/z)726(M⁺)542 ¹H NMR(CDCl₃) 1.25-1.33(4H, m)2.72(2H, brs)3.17 (2H, m)4.39(2H, s)5.33(2H, s)6.82- 6.91(3H, m)7.16(1H,m)7.30-7.58(10H, m)7.69(2H, dd J=6.75 1.8Hz)7.83-7.87 (3H, m) 20

—CH₂O—

4 FAB-MS: (m/z)690(M⁺)504 ¹H NMR(CDCl₃) 0.85-0.93(4H, m)1.13(4H, dJ=6.26Hz) 2.05(1H, br s)2.68(2H, br s)3.13 (2H, br s)4.38(2H, s)5.23(2H,s)6.70- 6.90(3H, m)7.13(1H, br s)7.30-7.90 (8H, m) 21

—CH₂O—

4 FAB-MS: (m/z)674(M⁺)490 353 244 ¹H NMR(CDCl₃) 0.82-0.99(4H, m)1.13(4H,d J=6.26Hz) 2.08(1H, m)2.75(2H, br s)3.12(2H, m)4.40(2H, s)5.23(1H, brs)6.81- 6.89(4H, m)7.07-7.17(3H, m)7.51-7.66 (3H, m)7.77-7.82(2H,m)7.90(1H, d J=7.26Hz) 22

—CH₂O—

4 FAB-MS: (m/z)736(M⁺+1)550 244 246 ¹H NMR(CDCl₃) 0.80-0.95(4H,m)1.18-1.23(4H, m)2.23 (1H, m)2.62(2H, br s)3.06(2H, br s) 4.33(2H,s)5.17(2H, s)6.88(4H, br s)7.12(1H, m)7.26-7.47(6H, m)77.56 (2H, dJ=8.58Hz)7.63(1H, d J=7.92Hz) 23

—CH₂O—

4 FAB-MS: (M/Z)656(M⁺)472 332 ¹H NMR(CDCl₃) 0.86-0.96(4H, m)1.25(4H,m)2.09(3H, m)2.76(2H, br s)3.15(2H, br s)4.39 2H, s)5.29(2H,s)6.83-6.90(4H, m) 7.14(1H, m)7.46-7.66(6H, m)7.80 (2H, dJ=7.26Hz)7.93(1H, d J=7.26Hz) 24

—CH₂O—

4 FAB-MS(m/z)670(M⁺)486 349 244 ¹H NMR(CDCl₃) 0.81-0.94(4H,m)1.24-1.32(4H, m)2.02- 2.12(1H, m)2.37(3H, s)2.73(2H, br s) 3.15(2H,m)4.39(2H, s)5.25(2H, s) 6.82-6.87(4H, m)7.11-7.26(4H, m) 7.47-7.67(5H,m)7.87(1H, d J=7.26Hz) 25

—CH₂O—

4 FAB-MS: (m/z)686(M⁺) ¹H NMR(CDCl₃) 0.84-0.99(4H, m)1.25-1.36(4H,m)2.09 (1H, m)2.74(2H, br s)3.15(2H, d J= 6.93Hz)3.84(3H, s)4.39(2H,s)5.01 (1H, br s)5.29(2H, s)6.82-6.94(6H m) 7.15(1H, tJ=7.92Hz)7.52-7.75(5H, m)7.93(1H, d J=7.59Hz) 26

—CH₂O—

3 FAB-MS: (m/z)676(M⁺)493 318 244 ¹H NMR(CDCl₃) 0.82-0.99(4H, m)1.40(2H,d J=5.94Hz) 2.08(1H, m)2.77(2H, br s)3.26(2H, m)4.38(2H, s)5.28(1H,s)5.66(1H, br s)6.80-6.88(4H, m)7.15(1H, m)7.39 (2H, dd J=6.921.98Hz)7.52-7.63 (3H, m)7.71(2H, dd J=6.93 1.98Hz)7.86 (1H d J=7.26Hz)27

—CH₂O—

2 FAB-MS: (m/z)662(M⁺)478 341 ¹H NMR(CDCl₃) 0.82-0.98(4H, m)2.09(1H,m)2.73(2H, br s)3.30(2H, t J=5.75Hz)4.35(2H, s)5.36(2H, s)6.02(1H, brs)6.78- 6.91(4H, m)7.13(1H, t J=7.76Hz)7.33 (2H, dJ=8.58Hz)7.53-7.67(5H, m)7.96 (1H, d J=7.59Hz) 28

—CH₂O—

2 FAB-MS: (m/z)646(M⁺) ¹H NMR(CDCl₃) 0.82-0.97(4H, m)2.09(1H, m)2.74(2H,br s)3.30(2H, t J=5.78Hz)4.35(2H, s)5.34(2H, s)5.94(1H, br s)6.78-6.89(4H, m)7.00-7.16(3H, m)7.53-7.65 (5H, m)7.95(1H, d J=7.92Hz) 29

—CH₂CH₂—

4 FAB-MS: (m/z)702(M⁺)518 256 244 ¹H NMR(CDCl₃) 1.20-1.40(4H,m)1.82-2.41(6H, m)2.75 (2H, br s)3.01(2H, t)3.14(2H, t) 3.31(2H,t)3.66(1H, quint)4.39(2H, s)5.38(1H, br s)6.77(1H, s)7.02-7.17 (4H,m)7.50-7.65(3H, m)7.71(2H, d J=8.58Hz)7.38(2H, d J=8.57Hz)7.90 (1H, dJ=7.26Hz) 30

—CH₂CH₂—

4 FAB-MS: (m/z)748(M⁺)670 564 ¹H NMR(CDCl₃) 1.20-1.40(4H,m)1.81-2.41(6H, m)2.73 (2H, br s)3.03(2H, m)3.13(2H, m) 3.32(2H,m)3.66(1H, quint)4.39(2H, s)5.38(1H, br s)6.77(1H, s)7.02- 7.16(5H,m)7.52-7.65(6H, m)7.89(1H, d J=7.59Hz) 31

—CH₂CH₂—

4 FAB-MS: (m/z)669(M⁺) ¹H NMR(CDCl₃) 0.82-0.99(4H, m)1.40(2H, dJ=5.94Hz) 2.08(1H, m)2.77(2H, br s)3.26(2H, m)4.38(2H, s)5.28(1H,s)5.66(1H, br s)6.80-6.88(4H, m)7.15(1H, m)7.39 (2H, dd J=6.921.98Hz)7.52-7.63 (3H, m)7.71(2H, dd J=6.93 1.98Hz)7.86 (1H d J=7.26Hz)32

—CH₂CH₂—

4 FAB-MS: (m/z)683(M⁺) ¹H NMR(CDCl₃ 1.20-1.40(4H, m)1.82-2.37(6H, m)2.39(3H, m)2.72(2H, m)3.01(2H, t)3.13 (2H, t)3.33(2H, t)3.67(1H, quint)4.38(2H, s)6.76(1H, d J=0.66Hz)7.04- 7.26(7H, m)7.51-7.68(4H, m)7.92(1H,d J=7.59Hz) 33

—CH₂CH₂—

4 FAB-MS: (m/z)674(M⁺) ¹H NMR(CDCl₃) 1.28(10H, m)2.70-2.78(2H,m)2.99-3.66 (4H, m)3.34(2H, m)4.39(2H, s)5.21 (1H, br t)6.74(1H,s)7.16(6H, m) .52-7.67(3H, m)7.77-7.82(2H, m) 7.91(1H, d J=7.59Hz) 34

—CH₂CH₂—

4 FAB-MS: (m/z)671(M⁺) ¹H NMR(CDCl₃) 1.28(10H, m)2.39(3H, s)2.68(2H, m)2.99-3.19(4H, m)3.34(2H, m)4.38(2H, s) 5.00(1H, br t)6.73(1H, s)7.03-7.26(6H, m)7.51-7.68(5H, m)7.92(1H, d J=7.26Hz) 35

4 FAB-MS(m/z)674(M⁺)645 ¹H NMR(CDCl₃) 1.23-1.35(4H, m)2.65(2H, br s)3.20(2H, br s)4.52(2H, s)5.77(1H, br s) 6.81-7.05(3H, m)7.15-7.17(2H, m)7.39-7.95(13H, m)8.25(2H, m) 36

4 FAB-MS: (m/z)734(M⁺)550 244 ¹H NMR(CDCl₃) 1.22-1.33(4H, m)2.63(2H, brs)3.19 (2H, br s)4.52(2H, s)5.96(1H, br s) 7.05-7.16(2H,m)7.38-7.93(16H, m) 8.25(2H, m) 37

4 FAB-MS: (m/z)686(M⁺)645 ¹H NMR(CDCl₃) 1.22-1.35(4H, m)2.66(2H, brs)3.21 (2H, br s)3.77(3H, s)4.52(2H, s)5.29 (1H, br s)6.82(2H,m)5.29(1H, br s) 6.82(2H, m)7.19(2H, d J=4.62Hz) 7.40-7.94(14H,m)8.25(2H, s) 38

4 FAB-MS: (m/z)670(M⁺) 645 553 ¹H NMR(CDCl₃) 1.19-1.32(4H, m)2.31(3H,s)2.63(2H, br s)3.19(2H, br s)4.50(2H, s)5.44 (1H, br s)7.26(4H,m)7.39-7.78(13H, m)7.87(1H, d J=7.92Hz)8.24(2H, m) 39

4 FAB-MS: (m/z)656(M⁺) ¹H NMR(CDCl₃) 1.20-1.32(4H, m)2.64(2H, br s)3.18(2H, br s)4.51(2H, s)5.58(1H, br s) 7.12-7.92(19H, m)8.24(2H, m) 40

3 FAB-MS: (m/z)676(M⁺) ¹H NMR(CDCl₃) 1.25-1.33(2H, m)2.63-2.70(2H,m)3.10- 3.21(4H, m)3.50(2H, t J=7.92Hz) 4.34(2H, s)6.17(1H, brs)6.99-7.14 (3H, m)7.26(4H, m)7.39-7.78(13H, m) 7.87(1H, dJ=7.92Hz)8.24(2H, m) 41

2 FAB-MS: (m/z)663d(M⁺)608 476 244 ¹H NMR(CDCl₃) 2.75(2H, s)3.30(2H,s)4.48(2H, s)5.98 (1H, br s)7.13(2H, m)7.43-7.93(14H, m)8.30(1H, dJ=8.57Hz)8.35(1H, d J=8.91Hz) 42

2 FAB-MS: (m/z)708(M⁺)522 244 ¹H NMR(CDCl₃) 2.73(2H, s)3.30(2H,s)4.48(2H, s)7.12 (2H, s)7.39-7.91(16H, m)8.27(1H, d J=8.58Hz)8.33(1H, dJ=8.91Hz) 43

2 FAB-MS: (m/z)646(M⁺)450 244 ¹H NMR(CDCl₃) 2.75(2H, s)3.31(2H,s)4.48(2H, s)6.96 (2H, t)7.11(2H, d J=4.29Hz)7.42- 7.92(14H, m)8.23(1H,d J=8.58Hz) 8.33(1H, d J=8.91Hz) 44

2 FAB-MS: (m/z)628(M⁺)483 ¹H NMR(CDCl₃) 2.87(2H, dd J=12.25.94Hz)3.37(2H, m)4.00(3H, s)4.45(2H, s)7.22-7.75 (17H, m)7.80(1H, dJ=7.92Hz)7.95(1H, dd J=6.1 1.5Hz)8.09Hz(1H, d J=8.25Hz) 8.16(1H, dJ=8.9Hz) 45

4 FAB-MS: (m/z)724(M⁺)675 ¹H NMR(CDCl₃) 1.21-1.40(4H, m)2.68-2.72(2H,m)3.22 (2H, br t J=6.93Hz)4.50(2H, s)5.59- 5.64(1H, m)7.18(2H, dJ=4.95Hz) 7.30-7.72(14H, m)7.89(1H, d J=7.59Hz) 8.13-8.17(2H, m) 46

4 FAB-MS(m/z)708(M⁺) ¹H NMR(CDCl₃) 1.22-1.42(4H, m)2.68-2.72(2H, m)3.21(2H, br t)4.50(2H, s)5.54-5.60(1H, m)7.00-7.06(2H, m)7.15-7.17(2H, m)7.41(2H, dd J=1.98 8.58Hz)7.47-7.78 (10H, m)7.88(1H, d J=7.26Hz)8.13-8.17(2H, m) 47

4 FAB-MS: (m/z)68(M⁺) ¹H NMR(CDCl₃) 1.21-1.40(4H, m)2.67-2.75(2H, m)3.21(2H, br t J=6.60Hz)4.50(2H, s)5.58- 5.63(1H, m)7.70(2H, d J=4.62Hz)7.38-7.66(12H, m)7.71(2H, d J=8.9Hz) 7.88(1H, d J=7.26Hz)8.13-8.17(2H,m) 48

4 FAB-MS: (m/z)720(M⁺) ¹H NMR(CDCl₃) 1.21-1.41(4H, m)2.67-2.74(2H,m)3.23 (2H, br t J=6.93Hz)3.78(3H, s)4.50 (2H, s)5.10-5.15(1H,m)6.86(2H, d J=8.91Hz)7.19-7.21(2H, m)7.44(2H dd J=1.818.75Hz)7.50-7.73(10H, m) 7.91(1H, d J=7.92Hz)8.08-8.17(2H, m) 49

4 FAB-MS: (m/z)704(M⁺) ¹H NMR(CDCl₃) 1.20-1.41(4H, m)2.32(3H,s)2.67-2.70 (2H, m)3.21(2H, br t J=6.93Hz)4.49 (2H, s)5.22-5.29(1H,m)7.12-7.21 (4H, m)7.41(2H, dd J=1.98 8.58Hz)7.47- 7.72(10H, m)7.89(1H,d J=7.92Hz) 8.07-8.16(2H, m) 50

4 FAB-MS: (m/z)690(M⁺) ¹H NMR(CDCl₃) 1.20-1.40(4H, m)2.67-2.75(2H,m)3.21 (2H, br t J=6.93Hz)4.50(2H, s)5.30- 5.37(1H, m)7.06(1H, dJ=6.27Hz) 7.18(2H, d J=4.62Hz)7.36-7.75(14H, m)7.90(1H, dJ=7.92Hz)8.13-8.16(2H, m) 51

3 FAB-MS: (m/z)710(M⁺) ¹H NMR(CDCl₃) 1.46-1.53(2H, m)2.51-2.60(2H,m)3.22 (2H, br t J=7.09Hz)4.48(2H, s)7.25 (1H, d J=7.26Hz)7.36-7.43(2H,m) 7.58-7.76(10H, m)7.82(1H, d J=16.2Hz) 7.93(2H, dJ=8.58Hz)7.98-8.06(2H, m) 8.41(1H, d J=8.91Hz) 52

2 FAB-MS: (m/z)696(M⁺) ¹H NMR(CDCl₃) 2.75-2.9(2H, m)3.30-3.35(2H, m)4.48(2H, s)7.14(2H, d J=4.29Hz)7.25- 7.29(2H, m)7.42-7.64(10H, m)7.70-7.77(2H, m)7.90(1H, d J=7.59Hz)8.22 (1H, d J=8.9Hz) 53

—CH₂O—

4 FAB-MS: (m/z)6.78(M⁺)494 248 ¹H NMR(CDCl₃) 1.10-1.28(4H,m)2.62-2.68(2H, m)3.07 (2H, br t J=6.60Hz)4.37(2H, s)5.36 (1H, brs)5.42(1H, s)6.78(1H, d J= 7.58Hz)6.91(1H, dd J=8.25Hz)7.00- 7.14(4H,m)7.45-7.76(8H, m)7.85(2H, t J=9.06Hz)8.22(2H, t J=7.43Hz) 54

—CH₂O—

4 FAB-MS: (m/z)737(M⁺) ¹H NMR(CDCl₃) 1.08-1.28(4H, m)2.58-2.66(2H,m)3.00- 3.10(2H, m)4.34(2H, s)5.33(2H, s) 6.77(1H, d J=7.25Hz)6.88(1H,dd J=8.25Hz)6.94(1H, s)7.10(1H, t)J= 7.75Hz)7.30-7.80(12H, m)8.12(1H, dJ=8.92Hz)8.17(1H, d J=8.25Hz) 55

—CH₂O—

4 FAB-MS: (m/z)690(M⁺) ¹H NMR(CDCl₃) 1.08-1.18(2H, m)1.20-1.31(2H, m)2.60-2.65(2H, m)3.03(2H t J=6.95Hz) 3.81(3H, s)4.36(2H, s)4.86 (1H, brs)5.46(2H, s)6.78(1H, d J= 7.58Hz)6.87-6.93(3H, m)7.02(1H, s) 7.12(1H, tJ=7.75Hz)7.49-7.61 (3H, m)7.67-7.91(5H, m)7.84(1H, d J=7.91Hz)7.93(1H, dJ=7.59Hz) 8.24-8.29(2H, m) 56

—CH₂O—

4 FAB-MS: (m/z)674(M⁺) ¹H NMR(CDCl₃) 1.07-1.16(2H, m)1.18-1.29(2H,m)2.36 (3H, s)2.59-2.65(3H, m)3.04(2H, t J=6.77Hz)4.35(3H,s)4.95-5.02(1H, m)5.44(2H, s)6.78(1H, d J=7.58Hz) 6.91(1H, ddJ=7.92Hz)7.01(1H, s)7.11 (1H, t J=7.76Hz)7.19(2H, d J=7.92Hz)7.47-7.78(8H, m)7.83(1H, d J=7.91Hz) 7.91(1H, d J=7.59Hz)8.24(2H, dJ=8.58Hz) 57

—CH₂O—

4 FAB-MS: (m/z)660(M⁺) ¹H NMR(CDCl₃) 1.05-1.15(2H, m)1.17-1.29(2H,m)2.60- 2.67(2H, m)3.02(2H, t J=6.93Hz) 4.35(2H, s)4.94-4.98(1H,m)5.50(2H, s)6.78(1H, d J=7.58Hz)6.93(1H, dd J=7.58Hz)7.05(1H,s)7.12(1H, t J= 7.92Hz)7.40-7.62(6H, m)7.69-7.80 (5H, m)7.85(1H, dJ=7.92Hz)7.95(1H, d J=7.92Hz)8.27-8.32(2H, m) 58

—CH₂O—

3 FAB-MS: (m/z)674(M⁺)539 ¹H NMR(CDCl₃) 1.25-1.37(2H, m)2.58-2.67(2H,m)3.14 (2H, t J=6.43Hz)4.34(2H, s)5.52(2H, s)6.55-6.63(1H, m)6.77(1H, dJ= 7.58Hz)6.93(1H, d J=7.91Hz)7.01(1H, m)7.12(1H, t J=7.92Hz)7.32(2H, dJ=8.58Hz)7.51-7.67(6H, m)7.71-7.90 (4H, m)8.30(2H, d J=8.57Hz) 59

—CH₂O—

2 FAB-MS: (m/z)666(M⁺) ¹H NMR(CDCl₃) 2.66(2H, br s)3.21(2H, brs)4.32(2H, br s)5.54(2H, br s)6.75(1H, d J= 6.93Hz)6.91(1H, dJ=8.58Hz)7.00(21H, s)7.10(1H, t J=7.75Hz)7.24-7.27 (2H, m)7.47-7.61(6H,m)7.75-7.93(4H, m)8.26-8.43(2H, m) 60

—CH₂O—

2 FAB-MS: (m/z)650(M⁺) ¹H NMR(CDCl₃) 2.65-2.70(2H, m)3.23(2H, br t)4.33(2H, s)5.50(2H, s)6.76(1H, d J=7.59 Hz)6.89-7.00(4H, m)7.10(1H, tJ=7.75Hz) 7.42-7.62(6H, m)7.73-7.92(4H, m) 8.23-8.32(2H, m) 61

—CH₂O—

2 FAB-MS: (m/z)710(M⁺) ¹H NMR(CDCl₃) 2.64-2.70(2H, m)3.21(2H, t,J=5.61Hz) 4.32(2H, s)5.57(2H, s)6.75(1H, d J=7.26Hz)6.92(1H, dd J=2.318.24Hz) 7.01(1H, s)7.11(1H, t J=7.92Hz)7.46 (4H, m)7.49-7.65(4H,m)7.77-7.95 (4H, m)8.28-8.36(2H, m) 62

—CH₂O—

2 FAB-MS: (m/z)633(M⁺) ¹H NMR(CDCl₃) 2.65-2.70(2H, m)3.18(2H, br tJ=5.61Hz) 4.29(2H, s 5.59(2H, s)6.73(1H, d J=7.59Hz)6.96(1H, dd J=1.988.25Hz) 7.00(1H, s)7.09(1H, t J=7.92Hz) 7.34(2H, tJ=7.43Hz)7.42-7.71(7H, m)7.76-7.84(2H, m)7.88(1H, d J=7.92Hz) 7.98(1H, dJ=7.59Hz)8.33(1H, d J=8.91Hz)8.34(1H, d J=8.25Hz) 63

—CH₂O—

5 FAB-MS: (m/z)721(M⁺) ¹H NMR(CDCl₃) 0.89-0.99(2H, m)1.11-1.27(4H,m)2.67- 2.74(2H, m)3.04(2H, t J=6.93Hz) 4.38(2H, s)5.42(2H, s)6.79(1H, dJ= 7.26Hz)6.91(1H, dd J=1.65 8.25Hz) 7.02(1H, s)7.13(1H, t J=7.92Hz)7.36(2H, d J=8.58Hz)7.47-7.78(8H, m) 7.84(1H, d J=8.24Hz)7.91(1H, dJ=7.59Hz) 8.24(2H, d J=8.58Hz) 64

—CH₂O—

2 FAB-MS: (m/z)700(M⁺) ¹H NMR(CDCl₃) 2.70-2.79(2H, m)3.26(2H, tJ=5.78Hz) 4.34(2H, s)5.47(2H, s)5.99-6.08(1H, m)6.78(1H, dJ=7.58Hz)6.91(1H, dd J=1.98 8.25Hz)6.98(1H, s)7.12(1H, tJ=7.92Hz)7.28(2H, d J=8.58Hz) 7.50-7.81(8H, m)7.93(1H, d J=7.26Hz)8.21(1H, d J=1.98Hz)8.27(1H, d J=8.58Hz) 65

—CH₂O—

4 FAB-MS: (m/z)730(M⁺) ¹H NMR(CDCl₃) 1.18-1.36(4H, m)2.68-2.74(2H,m)3.13 (2H, t J=6.76Hz)4.39(2H, s)6.80(1H, d J=7.59Hz)6.90(1H, ddJ=7.92Hz) 6.97(1H, m)7.14(1H, J=7.92Hz)7.35 (2H, dJ=8.58Hz)7.48-7.70(7H, m) 7.76(1H, d J=8.58Hz)7.88(1H, d J=7.26Hz)8.14(1H, d J=1.65Hz)8.20(1H, d J=8.58Hz) 66

—CH₂CH₂—

4 FAB-MS: (m/z)692(M⁺)600 508 246 ¹H NMR(CDCl₃) 1.10-1.30(4H,m)3.60-2.68(2H, m)3.05- 3.13(4H, m)3.44(2H, t J=7.92Hz) 4.38(2H,s)5.74-5.81(1H, m)7.01-7.11 (3H, m)7.26-7.37(4H, m)7.46(1H, t dJ=1.32-7.5Hz)7.53-7.68(5H, m)7.72- 7.88(3H, m)8.22(1H, d J=8.25Hz)8.34(1H, d J=8.58Hz) 67

—CH₂CH₂—

4 FAB-MS: (m/z)676(M⁺)492 246 ¹H NMR(CDCl₃) 1.14-1.30(4H,m)2.59-2.67(2H, m)3.08- 3.13(4H, m)3.44(2H, t J=7.92Hz) 4.38(2H,s)5.60-5.70(1H, m)6.99-7.13 (5H, m)7.26(1H, s)7.35(1H, d J=8.58Hz)7.43-7.64(4H, m)7.71-7.88(5H, m) 8.21(1H, d J=8.58Hz)8.34(1H, dJ=8.58Hz) 68

—CH₂CH₂—

4 MS: (m/z)672(M⁺)488 246 ¹H NMR(CDCl₃) 1.10-1.30(4H, m)2.34(3H,s)2.59-2.65 (2H, m)3.04-3.12(4H, m)3.42(2H, t J=7.75Hz)4.37(2H,s)5.25-5.32(1H, m) 7.00-7.12(3H, s)7.17(2H, d J=7.92Hz) 7.25(1H, dJ=7.59Hz)7.32(1H, d J=8.58Hz)7.42-7.64(6H, m)7.71-7.81 (2H, m)7.87(1H, dJ=7.26Hz)8.18 1H, d J=8.58Hz)8.34(1H, d J=8.25Hz) 69

—CH₂CH₂—

4 FAB-MS: (m/z)688(M⁺)596 504 246 ¹H NMR(CDCl₃) 1.09-1.33(4H,m)2.59-2.68(2H, m)3.04- 3.12(4H, m)3.42(2H, t J=7.75Hz) 3.79(3H,s)4.37(2H, s)6.85(2H, d J= 8.91Hz)7.00-7.12(3H, m)7.25(1H, dJ=6.27Hz)7.32(1H, d J=8.58Hz)7.42- 7.58(3H, m)7.62-7.81(5H, m)7.88(1H, dJ=7.26Hz)8.18(1H, d J=8.58Hz) 8.24(1H, d J=8.58Hz) 70

—CH₂CH₂—

4 FAB-MS: (m/z)736(M⁺)552 246 ¹H NMR(CDCl₃) 1.11-1.29(4H,m)2.58-2.64(2H, m)3.07- 3.12(4H, m)3.43(2H, t J=7.75Hz) 4.37(2H,s)5.78-5.82(1H, m)7.01-7.13 (3H, m)7.25(1H, d J=2.97Hz)7.34(1H, dJ=8.54Hz)7.42-7.47(3H, m)7.52- 7.62(5H, m)7.71-7.87(3H, m)8.21(1H, dJ=8.58Hz)8.33(1H, d J=8.58Hz) 71

—CH₂CH₂—

2 FAB-MS: (m/z)664(M⁺)480 246 ¹H NMR(CDCl₃) 2.57-2.69(2H,m)2.99-3.07(2H, m)3.10- 3.18(2H, m)3.18-3.27(2H, m)4.41(2H,m)7.00-7.04(1H, m)7.09(1H, br s) 7.18-7.21(2H, m)7.41(1H, d J=8.25Hz)7.52-7.79(9H, m)7.85-8.00(3H, m) 8.25(1H, d J=8.58Hz) 72

—CH₂CH₂—

3 FAB-MS: (m/z)678(M⁺) ¹H NMR(CDCl₃) 1.25-1.33(2H, m)2.63-2.70(2H,m)3.10- 3.21(4H, m)3.50(2H, t J=7.92Hz) 4.34(2H, s)6.17-6.24(1H,m)6.99-7.14 (3H, m)7.26-7.33(3H, m)7.40(1H, d J= 8.58Hz)7.48(1H, t dJ=7.59 1.54Hz) 7.56-7.67(5H, m)7.79-7.88(3H, m) 8.27(1H, dJ=8.58Hz)8.42(1H, d J=8.58Hz) 73

—CH₂CH₂—

5 FAB-MS: (m/z)706(M⁺)672 ¹H NMR(CDCl₃) 0.89-1.01(2H, m)1.09-1.25(4H,m)2.64- 2.72(2H, m)3.02-3.14(4H, m)3.47 (2H, t J=7.75Hz)4.38(2H,s)5.63-5.70 (1H, m)7.00-7.13(3H, m)7.26-7.29 (1H, m)7.36(2H, dJ=7.26Hz)7.44-7.83 (9H, m)7.91(1H, d J=7.26Hz)8.23(1H, dJ=8.58Hz)8.41(1H, d J=8.58Hz) 74

—CH₂CH₂—

4 FAB-MS: (m/z)726(M⁺)542 383 280 ¹H NMR(CDCl₃) 1.18-1.35(4H, m)2.69(2H,br d J=4.62Hz) 3.05-3.13(4H, m)3.35(2H, t J=7.76Hz) 4.37(1H,s)5.42-5.50(1H, m) 7.01-7.15(3H, m)7.20(1H, m)7.28-7.36 (3H,m)7.44-7.74(7H, m)7.87(1H, d J= 7.59Hz)8.11(1H, d J=8.58Hz)8.21 (1H, dJ=1.32Hz) 75

—CH₂CH₂—

4 FAB-MS: (m/z)710(M⁺)526 228 ¹H NMR(CDCl₃) 1.19-1.37(4H, m)2.70(2H, brd J=4.95Hz) 3.05-3.15(4H, m)3.36(2H, br t J=7.76Hz)4.38(2H,s)5.35-5.42(1H, m) 7.02-7.15(5H, m)7.21(1H, s)7.23 1H, dJ=8.25Hz)7.44-7.78(7H, m)7.87 (1H, d J=7.59Hz)8.12(1H, d J=8.25Hz)8.21(1H, s) 76

—CH₂CH₂—

4 FAB-MS: (m/z)706(M⁺)614 522 349 ¹H NMR(CDCl₃) 1.15-1.38(4H, m)2.37(3H,s)2.67-2.73 (2H, m)3.05-3.13(4H, m)3.34(2H, t 7.92Hz)4.37(2H,s)5.05-5.13(1H, m) 7.01-7.14(3H, m)7.20-7.30(4H, m)7.44- 7.69(6H,m)7.72(1H, d J=8.58Hz) 7.90(1H, d J=7.92Hz)8.05(1H, d J=8.25Hz) 8.20(1H,d J=1.98Hz 77

—CH₂CH₂—

4 FAB-MS: (m/z)722(M⁺)688 538 ¹H NMR(CDCl₃) 1.15-1.39(4H,m)2.63-2.71(2H, m)3.04- 3.13(4H, m)3.34(2H, t J=7.92Hz) 3.80(3H,s)4.37(2H, s)6.88(2H, d J= 8.91Hz)7.01-7.14(3H, m)7.19(1H, s) 7.28(1H, dJ=8.58Hz)7.43-7.73(7H, m) 7.88(1H, d J=7.59Hz)8.09(1H, d J=8.58Hz)8.21(1H, d J=1.65Hz) 78

—CH₂CH₂—

4 FAB-MS: (m/z)770(M⁺) ¹H NMR(CDCl₃) 1.12-1.32(4H, m)2.65-2.72(2H,m)3.05- 3.15(4H, m)3.35(2H, t J=7.92Hz) 4.38(2H, s)7.02-7.15(3H,m)7.20(1H, s)7.30(1H, d J=8.58Hz)7.45-7.53(4H, m)7.56-7.66(4H,m)7.73(1H, d J= 8.58Hz)7.56-7.66(4H, m)7.73(1H, d J=8.58Hz)7.86(1H, dJ=7.26Hz)8.12 (1H, d J=8.25Hz)8.21(1H, d J=1.98Hz 79

—CH₂CH₂—

2 FAB-MS: (m/z)699(M⁺) ¹H NMR(CDCl₃) 2.70-2.77(2H, m)3.10(2H, tJ=7.75Hz) 3.23-3.28(2H, m)3.43(2H, t J=7.91Hz) 4.35(2H, s)6.99-7.13(3H,m)7.26- 7.29(3H, m)7.36(1H, d J=8.58Hz)7.48- 7.54(4H, m)7.57-7.64(2H,m)7.76 (1H, d J=8.91Hz)7.91(1H, d J=7.92Hz) 8.18(1H, d J=8.58Hz)8.26(1H,d J=1.65Hz) 80

—CH₂CH₂—

3 FAB-MS: (m/z)712(M⁺)528 ¹H NMR(CDCl₃) 1.28-1.38(2H, m)2.68-2.75(2H,m)3.09 (2H, t J=7.76Hz)3.20-3.25(2H, m) 3.39(2H, t J=7.92Hz)4.35(2H,s)5.86 (1H, br t)7.00-7.15(3H, m)7.25-7.26 (2H, m)7.33(2H, dJ=8.58Hz)7.48- 7.56(2H, m)7.59-7.68(4H, m)7.76(1H, d J=8.91Hz)7.86(1H, dJ=7.92Hz)8.17 (1H, d J=8.58Hz)8.27(1H, d) 81

—CH₂O—

5 FAB-MS: (m/z)703(M⁺)669 519 ¹H NMR(CDCl₃) 1.11-1.19(2H,m)1.25-1.36(2H, m)1.47- 1.58(2H, m)1.85-2.13(2H, m)2.17- 2.31(2H,m)2.34-2.45(2H, m)2.87-2.96 (2H, m)3.10(2H, t J=7.26Hz)3.74 (1H, quintJ=8.49Hz)4.39(2H, s)5.38 (2H, s)6.80-6.88(2H, m)6.94-6.96(2H, m)7.13(1H,t J=7.92Hz)7.50-7.70 (5H, m)7.79(2H, d J=8.58Hz)7.96(1H, d J=7.59Hz) 82

—CH₂O—

5 FAB-MS: (m/z)689(M⁺)655 505 244 ¹H NMR(CDCl₃) 0.83-0.91(2H,m)0.91-1.00(2H, m)1.14- 1.22(2H, m)1.26-1.38(2H, m)1.51- 1.62(2H,m)2.707-2.17(1H, m)2.91-2.97 (2H, m)3.12(2H, t J=7.26Hz)4.39 (2H,s)5.30(2H, s)6.81-6.88(3H, m) 6.93(1H, br s)7.15(1H, t J=7.92Hz)7.52(2H,d J=8.57Hz)7.56-7.71(3H, m) 7.81(2H, d J=8.58Hz)7.95(1H, d J= 7.59Hz) 83

—CH₂O—

5 FAB-MS: (m/z)691(M⁺)657 507 473 ¹H NMR(CDCl₃) 1.11-1.19(2H,m)1.26-1.33(8H, m)1.47- 1.59(2H, m)2.88-2.94(2H, m)3.08- 3.13(2H,m)3.19(1H, quint J=6.93Hz) 4.39(2H, s)5.38(2H, s)6.81-6.88(2H,s)6.93(1H, s)6.95(1H, br s)7.13 (1H, t J=7.92Hz)7.52(2H, d J=8.58Hz)7.56-7.70(3H, m)7.79(2H, d J=8.58Hz) 7.96(1H, d J=7.59Hz) 84

5 FAB-MS: (m/z)689(M⁺)244 ¹H NMR(CDCl₃) 1.18-1.11(2H, m)1.22-1.39(2H,m)1.42- 1.50(2H, m)2.8-2.84(2H, m)3.20 (2H, br t J=7.78Hz)4.50(2H,s)7.14- 7.16(2H, s)7.42-7.82(15H, m)7.91(1H, d J=7.26Hz)8.22-8.27(2H, m)85

5 FAB-MS: (m/z)723(M⁺) ¹H NMR(CDCl₃) 1.17-1.23(2H, m)1.24-1.37(2H,m)1.42- 1.55(2H, m)2.82-2.87(2H, m)3.21 (2H, br t J=6.93Hz)4.50(2H,s)7.17- 7.22(2H, m)7.42-7.88(14H, m)7.91(1H, d J=7.59Hz)8.13-8.16(2H, m)86

—CH₂CH₂—

5 FAB-MS: (m/z)691(M⁺)507 ¹H NMR(CDCl₃) 1.05-1.15(2H, m)1.21-1.32(2H,m)1.41- 1.51(2H, m)2.81-2.88(2H, m)3.01- 3.18(4H, m)3.37-3.45(2H,m)4.37(2H, s) 6.97-7.07(3H, m)7.26-7.31(2H, m) 7.47-7.61(5H,m)7.67-7.82(5H, m) 7.92(1H, d J=7.26Hz)8.16(1H, d J=8.25Hz) 8.36(1H, dJ=8.25Hz) 87

—CH₂CH₂—

5 FAB-MS: (m/z)725(M⁺) ¹H NMR(CDCl₃) 1.08-1.18(2H, m)1.22-1.23(2H,m)1.45- 1.56(2H, m)2.85-2.91(2H, m)3.04- 3.12(4H, m)3.38(2H, tJ=7.76Hz)4.38 (2H, s)6.99-7.15(3H, m)7.20-7.28 (2H, m)7.44-7.68(5H,m)7.68-7.83(4H, m)7.92(1H, d J=6.93Hz)8.08(1H, d J=8.58Hz)8.24(1H, dJ=1.65Hz) 88

—CH₂O—

5 FAB-MS: (m/z)693(M⁺) ¹H NMR(CDCl₃) 0.95-1.06(2H, m)1.16-1.27(2H,m)1.37- 1.49(2H, m)2.81-2.86(2H, m)3.01 (2H, t J=7.43Hz)4.35(2H,s)5.46(2H, s)6.77(1H, d J=7.58Hz)6.90(1H, dd J=1.82 8.08Hz)7.03(1H,s)7.11(1H, t J=7.76Hz)7.47-7.64(5H, m)7.69- 7.80(5H, m)7.85(1H, dJ=7.91Hz)7.96 (1H, dd J=1.49 7.765Hz)8.25-8.31(2H, m) 89

—CH₂O—

4 FAB-MS: (m/z)694(M⁺)510 248 ¹H NMR(CDCl₃) 1.10-1.27(4H,m)2.61-2.68(2H, m)3.07 (2H, br t J=6.93Hz)4.37(2H, s)5.44 (2H,s)6.78(1H, d J=7.25Hz)6.91(1H, d J=8.24Hz)7.00(1H, s)7.09-7.15(1H, m)7.32(2H, d J=8.91Hz)7.46-7.78(8H, m)7.82-7.89(2H, m)8.21-8.26(2H, m) 90

4 FAB-MS: (m/z)690(M⁺)506 244 ¹H NMR(CDCl₃) 1.20-1.39(4H,m)2.60-2.67(2H, m)3.15- 3.21(2H, m)4.51(2H, s)5.98-6.02(1H, brs)7.03-7.17(2H, m)7.25-7.31(2H, m) 7.36(1H, d J=7.26Hz)7.43-7.79(12H, m)7.86(1H, d J=7.59Hz)8.23-8.30(2H, m)

Example 12 Preparation of ethyl2-{N-[4-(4-chlorobenzenesulfonylamino)butyl]-N-{3-[(4-isopropyl-2-thiazoyl)methoxy]benzyl}}sulfamoylbenzoate(Compound No.1c)

2.15 g (3.11 mmol) of2-{N-[4-(4-chlorobenzenesulfonylamino)butyl]-N-{3-[(4-isopropyl-2-thiazolyl)methoxy]benzyl}}sulfamoylbenzoicacid (Compound No.1) was mixed with 16 ml of 1,2-dichloroethane and 0.41ml (4.7 mmol) of oxalyl chloride and stirred in the presence of acatalytic amount of N,N-dimethylmamide at room temperature. The reactionsolution was evaporated in vacuo for removal of the solvent and stirredtogether with 12 ml of ethanol, 12 ml of 1,2-dichloroethane and 0.65 ml(4.66 mmol) of triethylamine at room temperature for 1 hour. Thereaction solution was mixed with water and saturated aqueous sodiumhydrogen carbonate for neutralization and then extracted withchloroform. The chloroform layer was washed with saturated aqueoussodium chloride, dried over anhydrous magnesium sulfate and evaporatedin vacuo for removal of the solvent. The residue was purified by silicagel column chromatography (eluent; n-hexane:ethyl acetate=3:1) to give1.42 g of the title compound in a yield of 63.5%.

¹H-NMR(CDCl₃): 1.23-1.41(13H,m) 2.82(2H,m) 3.06-3.17(3H,m)4.38-4.45(4H,m) 4.83(1H,t) 5.26(2H,s) 6.90(4H,d J=0.66 Hz) 7.22(1H,m)7.45(2H,d J=1.98 6.6 Hz) 7.51-7.65(3H,m) 7.74(2H,d J=1.98 6.6 Hz)7.83(1H,m).

Similarly, the compounds of Examples 13 and 14 were prepared.

Example 13 Preparation of ethyl2-{N-[4-(4-methylbenzenesulfonylamino)butyl]-N-{3-[(4-cyclobutyl-2-thiazolyl)methoxy]benzyl}}sulfamoylbenzoate(Compound No.5c)

¹H-NMR(CDCl₃): 1.22-1.41(7H,m) 1.84-2.39(6H,m) 2.41(3H,s) 2.80(2H,m)3.16(2H,m) 3.67(1H,quint) 4.37-4.45(4H,m) 4.61(1H,t J=6.27 Hz)5.27(2H,s) 6.88-6.92(4H,m) 7.22-7.29(3H,m) 7.50-7.62(3H,m) 7.68(2H,dJ=8.24 Hz) 7.82(1h,d J=7.25 Hz).

Example 14 Preparation of ethyl2-{N-[4-(4-chlorobenzenesulfonylamino)butyl]-N-{3-[4-cyclobutyl-2-thiazolyl)ethyl]benzyl}}sulfamoylbenzoate(Compound No.29c)

¹H-NMR(CDCl₃): 1.21.41(7H,m) 1.87-2.39(6H,m) 2.80(2H,m) 3.14(2H,br s)3.22(2H,m) 4.40(4H,m) 5.04(1H,t J=5.94 Hz) 6.75(1H,s) 7.08(3H,m)7.20(1H,m) 7.45(2H,dd J=6.6 1.98 Hz) 7.51-7.65(3H,m) 7.73(2H,d J=8.25Hz) 7.82(1H,d J=8.24 Hz).

Example 15 Preparation of5-{2-{N-[4-(4-chlorobenzenesulfonylamino)butyl]-N-{3-[(4-isopropyl-2-thiazolyl)methoxylbenzyl}}sulfamoylphenyl}-1H-tetrazole(Compound No.91)

3.5 g (6.4 mmol) of the hydrochloride of the product in Example 9(Compound 1a) was dissolved in 75 ml of 1,2-dichloroethane and stirredtogether with 2.7 ml of triethylamine and 1.7 g (1.3 eq) of2-chlorosulfonylbenzonitrile at room temperature overnight. The organiclayer was washed with water and saturated aqueous sodium chloride, driedover anhydrous magnesium sulfate and evaporated in vacuo for removal ofthe solvent. The residue was purified by silica gel columnchromatography (eluent; chloroform to chloroform:methanol=99:1) to give3.9 g of2-{N-[4-(4-chlorobenzenesulfonylamino)butyl]-N-{3-[(4-isopropyl-2-thiazolyl)methoxylbenzyl}}sulfamoylbenzonitrile(Compound No.91b) in a yield of 89%.

FAB=MS(m/z): 673(M+); ¹H-NMR(CDCl₃): 1.32(6H,d,J=6.93Hz),1.42(4H,m),2.85(2H,m),3.11(1H,m),3.29(2H,m),4.42(2H,m),4.62(1H,m),5.29(2H,s),6.84-6.89(3H,m),6.91(1H,s),7.22(1H,m),7.47(2H,dd,J=8.58,1.82 Hz),7.65-7.78(4H,m),7.88(1H,dd,J=1.98,7.26 Hz),8.07(1H, m).

3.8 g (5.6 mmol) of the above-mentioned product (Compound No.91b) wasdissolved in 100 ml of toluene and stirred together with 3.7 ml (5.0 eq)of trimethylsilyl azide and 702 mg (0.5 eq) of dibutyltin oxide underheating at 70° C. for 28 hours. The solvent was distilled off in vacuo,and 50 ml of 1N sodium hydroxide and 50 ml of water were added to theresidue. The insolubles were filtered out, and the filtrate was washedwith 100 ml of ether. The aqueous layer was acidified with 6Nhydrochloric acid and extracted with chloroform. The solvent wasdistilled off in vacuo, and the residue was purified by silica gelcolumn chromatography (eluent; chloroform tochloroform:methanol=99:1-95:5) to give 3.1 g of an oily substance in ayield of 78%. The oily substance was dissolved in 8.4 ml of 1N sodiumhydroxide and 50 ml of water and acidified (pH 3.0) with iN hydrochloricacid, and the deposited precipitate was filtered off to give 2.4 g ofthe title compound (Compound No.91).

FAB-MS(m/z): 716(M+); ¹H-NMR(CDCl₃): 1.16(4H,m),1.27(6H,d,J=6.93Hz),2.73(2H, m),2.87(2H,m),3.07(1H,m),4.08(2H,s),5.30(2H,m),6.74-6.91(4H,m),7.20(1H,t,J=7.76 Hz),7.46(2H,m),7.68-7.80(4H,m),7.97(1H,dd,J=1.65,7.32 Hz),8.08(1H,dd,J=1,65,5.66 Hz).

Test Examples

Next, the excellent antagonistic effects on the receptors for bothmediators LTD₄ and TXA₂ and anti-allergic effects of the2-sulfamoylbenzoic acid derivatives of the present invention will bedemonstrated by referring to Test Examples.

Compounds of the present invention were tested on the LTD₄ inhibitoryeffects, TXA₂ inhibitory effects and antiasthmatic effects. The testprocedures and the test results were as follows.

Test Example 1

(LTD₄ antagonistic effects)

Guinea pigs were bled to death, and the ilea were excised and made intoileum preparations. The ileum preparations were suspended with a 1 gload in Magnus tubes filled with 2 ml Tyrode solution maintained at 37°C. under aeration with a 95% O₂-5% CO₂ gas mixture, and LTD₄-inducedconstrictions were isotonically recorded.

After equilibration of the tonuses of the ilea, constrictive responsesto cumulative addition of 0.05-3.5 ng/ml LTD₄ were observed. After theconstrictive responses reached equilibrium, LTD₄ was added againcumulatively 5 minutes after pre-treatment with a test substance toinduce constriction. The pA₂ values were calculated in accordance withVan Rossum's method. The results are shown below in Table 4.

Test Example 2

(TXA₂ antagonistic effects)

Guinea pigs were bled to death, and the tracheae were excised and madeinto tracheal muscle strips in accordance with Takagi et al. The stripswere suspended with a 1 g load in Magnus tubes filled with 2 ml Tyrodesolution maintained at 37° C. under aeration with a 95% O₂-5% CO₂ gasmixture, and U-46619-induced constrictions were isotonically recorded.

After equilibration of the tonuses of the strips, constrictive responsesto cumulative addition of 10⁻¹⁰-10⁻⁷M U-46619 were observed. After theconstrictive responses reached equilibrium, U-46619 was added againcumulatively 5 minutes after pre-treatment with a test substance toinduce constriction. The pA₂ values were calculated in accordance withVan Rossum's method. The results are shown below in Table 4.

These results demonstrate the excellent antagonistic effects ofcompounds of the present invention on the receptors for both mediatorsLTD₄ and TXA₂.

TABLE 4 Results of Test Examples 1 and 2 Compound LTD₄ inhibitory TXA₂inhibitory No. effect (pA₂) effect (pA₂)  1 9.73 8.30  2 9.59 7.99  39.26 8.12 13 9.92 7.90 14 9.92 8.06 15 9.47 8.03 16 10.03 7.99 17 9.807.97 20 9.43 8.17 21 9.65 7.99 22 9.45 8.31 24 9.65 8.17 29 9.92 7.90 539.82 8.69 54 9.71 7.90 55 9.82 8.78 71 9.12 8.40 72 9.58 8.05 91 9.057.73

Test Example 3

Antiasthmatic Effects

The antiasthmatic effects were evaluated by the immediate asthmaticresponses of passively sensitized guinea pigs. The previous day, theguinea pigs were sensitized by intravenous injections of a 10-folddiluted anti-DNP-ovalbumin guinea pig serum (guinea pig PCA titer;×1024) on the ears. The day of the test, after pre-treatment withpyrilamine (10 mg/kg i.p.), normal airway resitances were measured witha double flow plethysmograph in accordance with Pennock et al. The testsubstances (3 mg/kg) in DMSO were dissolved in 50% normal guinea pigserum-saline and intravenously injected from the ear vein 5 minutesbefore inhalation of the antigen. Immediate asthmatic responses wereinduced by 3 minutes of inhalational exposure to 1% ovalbumin in salineas the antigen from an ultrasonic neblizer, and the airway resistanceswere measured 5 minutes (4 to 6 minutes) after the inhalation. Theresults are expressed by the inhibition rates given by the followingexpression:

Inhibition rate (%)=(1−(A−B)/(C−D))×100

wherein A: the airway resistance with a test substance after inhalationof the antigen,

B: the airway resistance with a test substance before inhalation of theantigen,

C: the airway resistance with a control after inhalation of the antigen,

D: the airway resistance with a control before inhalation of theantigen.

The results are shown below in Table 5. These results demonstrate theexcellent antiasthmatic effects of compounds of the present invention.

TABLE 5 Results of Test Example 3 Compound No. Antiasthmatic effectInhibition rate (%)  1 53.5 24 40.5 38 59.5 70 54.0 [Acute toxicitytest]

Compounds Nos. 1, 5 and 29 were administered to ICR mice intravenouslyin an amount of 100 mg/kg and orally in an amount of 1000 mg/kg, butnone of the mice died.

Formulation Examples

Now, formulation examples using compounds of the present invention willbe given below. However, the present invention is by no means restrictedby these formulations.

Formulation Example 1

Tablets each containing 100 mg of an active ingredient were prepared inaccordance with the following formulation.

(Ingredients) (mg) Compound No. 1 100 Lactose 30 Corn starch 40Crystalline cellulose 15 Methylcellulose 3 Magnesium stearate 2

Formulation Example 2

A capsule drug was prepared by encapsulating 190 mg of an ingredientmixture containing 100 mg of an active ingredient in accordance with thefollowing formulation.

(Ingredients) (mg) Compound No. 1 100 Lactose 50 Corn starch 30Crystalline cellulose 8 Magnesium stearate 2

INDUSTRIAL APPLICABILITY

The novel 2-sulfamoylbenzoic acid derivatives represented by generalformula (I) of the present invention are both an antagonistic effect onthe LTD₄ receptor and an antagonistic effect on the TXA2 receptor andshow an excellent antiasthmatic effect. Therefore, the compounds of thepresent invention are useful as anti-allergic agents for treatment andprevention of various allergic diseases such as allergic bronchialasthma.

What is claimed is:
 1. A 2-sulfamoylbenzoic acid derivative representedby general formula (I):

wherein R1 and R2 which may be the same or different, are hydrogenatoms, C₃₋₈ cycloalkyl groups, optionally substituted C₁₋₆ alkyl groups,optionally substituted aryl groups or form, together with the ring

a condensed ring represented by formula

which may be substituted with an optionally substituted C₁₋₆ alkylgroup, an amino group, a cyano group, a nitro group, a hydroxyl group, ahalogen atom or a C₁₋₅ alkoxy group, X is an oxygen atom, a nitrogenatom, a sulfur atom or —CH═CH—, R3 is an optionally substitutedphenylsulfonylamino group, an optionally substituted phenylsulfonylgroup or an optionally substituted phenylsulfoxide group, R4 is ahydrogen atom or an ester residue, n is an integer of from 2 to 6, A is—O—B—, —B—O—, —S—B—, —B—S— or —B—, and B is a C₁₋₆ alkylene group or aC₂₋₅ alkenylene group, provided that the cases wherein R1 is a C₁₋₆alkyl group, a C₃₋₈ cycloalkyl group or a phenyl group, R2 is a hydrogenatom, A is a vinylene group, and X is a sulfur atom are excluded) or apharmaceutically acceptable salt, hydrate or solvate thereof.
 2. The2-sulfamoylbenzoic acid derivative according to claim 1 or apharmaceutically acceptable salt, hydrate or solvate thereof, wherein inthe general formula (I), X is a sulfur atom, and A is a —CH₂O— or anethylene group.
 3. The 2-sulfamoylbenzoic acid derivative according toclaim 2 or a pharmaceutically acceptable salt, hydrate or solvatethereof, wherein in the general formula (I), R1 and R2 which may be thesame or different groups and are selected from the group consisting ofhydrogen atoms, C₃₋₈ cycloalkyl groups, optionally substituted C₁₋₆alkyl groups and optionally substituted aryl groups.
 4. A2-sulfamoylbenzoic acid derivative or a pharmaceutically acceptablesalt, hydrate or solvate thereof, selected from the group consisting of2-{N-[4-(4-chlorobenzenesulfonylamino)butyl]-N-{3-[(4-isopropyl-2-thiazolyl)methoxy]benzyl}}sulfamoylbenzoicacid,2-{N-[4(4-methylbenzenesulfonylamino)butyl]-N-{3-[(4-isopropyl-2-thiazolyl)methoxy]benzyl}}sulfamoylbenzoicacid,2-{N-[4-(4-methoxybenzenesulfonylamino)butyl]-N-{3-[(4-isopropyl-2-thiazoyl)methoxy]benzyl}}sulfamoylbenzoicacid,2-{N-[4-(4-bromobenzenesulfonylamino)butyl]-N-{3-[(4-isopropyl-2-thiazolyl)methoxy]benzyl}}sulfamoylbenzoicacid,2-{N-[4-(4fluorobenzenesulfonylamino)butyl]-N-{3-[(4-isopropyl-2-thiazolyl)methoxy]benzyl}}sulfamoylbenzoicacid,2-{N-[4-(4-chlorobenzenesulfonylamino)butyl]-N-{3-[(4-cyclobutyl-2-thiazolyl)methoxy]benzyl}}sulfamoylbenzoicacid,2-{N-[4-(4-bromobenzenesulfonylamino)butyl]-N-{3-[(4-cyclobutyl-2-thiazolyl)methoxy]benzyl}}sulfamoylbenzoicacid,2-{N-[4-(4-fluorobenzenesulfonylamino)butyl]-N-{3-[(4-cyclobutyl-2-thiazolyl)methoxy]benzyl}}sulfamoylbenzoicacid,2-{N-[4-(benzenesulfonylamino)butyl]-N-{3-[(4-cyclobutyl-2-thiazolyl)methoxy]benzyl}}sulfamoylbenzoicacid,2-{N-[4-(4-methylbenzenesulfonylamino)butyl]-N-{3-[(4-cyclobutyl-2-thiazoyl)methyl]bezyl}}sulfamoylbenzoicacid,2-{N-[-(4-methoxybenzensulfonylamino)butyl]-N-{3-[(4-cyclobutyl-2-thiazolyl)methoxy]benzyl}}sulfamoylbenzoicacid,2-{N-[4(4-chlorobenzenesulfonylamino)butyl]-N-{3-[2-(4-cyclopropyl-2-thiazolyl)methoxy]benzyl}}sulfamoylbenzoicacid,2-{N-[5-(4-chlorobenzenesulfonylamino)pentyl]-N-{3-[2-(4-cyclobutyl-2-thiazolyl)methoxy]benzyl}}sulfamoylbenzoicacid,2-{N-[5-(4-chlorobenzenesulfonylamino)pentyl]-N-{3-[(4-isopropyl-2-thiazolyl)methoxy]benzyl}}sulfamoylbenzoicacid,2-{N-[4-(4-chlorobenzenesulfonylamino)butyl]-N-{3-[2-(4-cyclobutyl-2-thiazolyl)ethyl]benzyl}}sulfamoylbenzoicacid,2-{N-[4-(4-fluorobenzenesulfonylamino)butyl]-N-{3-[2-(4-cyclobutyl-2-thiazolyl)ethyl]benzyl}}sulfamoylbenzoic acid, and2-{N-4-(4-bromobenzenesulfonylamino)butyl]-N-{3-[2-(4-cyclobutyl-2-thiazolyl)ethyl]benzyl}}sulfamoylbenzoic acid.
 5. The 2-sulfamoylbenzoic acidderivative according to claim 1 or a pharmaceutically acceptable salt,hydrate or solvate thereof, wherein in the general formula (I), X is—CH═CH—, and A is selected from the group consisting of —CH₂O—, anethylene group, and a vinylene group.
 6. The 2-sulfamoylbenzoic acidderivative according to claim 1 or a pharmaceutically accepabe salt,hydrate or solvate thereof, wherein in the general formula (I), R1 andR2 form together with the ring

a condensed ring represented by formula

which may be substituted with a group selected from an optionallysubstituted C₁₋₆ alkyl group, an amino group, a cyano group, a nitrogroup, a hydroxyl group, a halogen atom, and C₁₋₅ alkoxy group.
 7. A2-sulfamoylbenzoic acid derivative or a pharmaceutcally acceptable salt,hydrate or solvate thereof selected from the group consisting of2-{N-[4-(4-chlorobenzenesulfonylamino)butyl]-N-{3-[2-(2-guinolyl)ethyl]benzyl}}sulfamoylbenzoicacid,2-{N-[4-(4-bromobenzenesulfonylamino)butyl]-N-{3-[2-(2-guinolyl)ethyl]benzyl}}sulfamoylbenzoicacid,2-{N-[4-(4-fluorobenzenesulfonylamino)butyl]-N-{3-[2-(2-guinolyl)ethyl]benzyl}}sulfamoylbenzoicacid,2-{N-[4-(4-methylbenzenesulfonylamino)butyl]-N-{3-2-(2-guinolyl)ethyl]benzyl}}sulfamoylbenzoicacid,2-{N-[4-(4-methoxybenenesulfonylamino)butyl]-N-{3-[2-(2-guinolyl)ethyl]benzyl}}sulfamoylbenzoicacid,2-{N[4-benzenesulfonylamino)butyl]-N-{3-[2-(2-guinolyl)ethyl]benzyl}}sulfamoylbenzoicacid,2-{N-[4-(4-chlorobenzenesulfonylamino)butyl]-N-{3-[2-(7-chloro-2-guinolyl)ethyl]benzyl}}sulfamoylbenzoicacid,2-{N-[4-(4-bromobenzenesulfonylamino)butyl]-N-{3-[2-(7-chloro-2-guinolyl)ethyl]benzyl}}sulfamoylbenzoicacid,2-{N-[4-(4-fluorobenzenesulfonylamino)butyl]-N-{3-[2-(7-chloro-2-guinolyl)ethyl]benzyl}}sulfamoylbenzoicacid,2-{N-[4-(4-methylbenzenesulfonylamino)butyl]-N-{3-[2-(7-chloro-2-guinolyl)ethyl]benzyl}}sulfamoylbenzoicacid,2-{N-[4-(4-methoxybenzenesulfonylamino)butyl]-N-{3-[2-(7-chloro-2-guinolyl)ethyl]benzyl}}sulfamoylbenzoicacid,2-{N-[4-(benzenesulfonylamino)butyl]-N-{3-[2-(7-chloro-2-guinolyl)ethyl]benzyl}}sulfamoylbenzoicacid,2-{N-[5-(4-chlorobenzenesulfonylamino)pentyl]-N-{3-[2-(7-chloro-2-guinolyl)ethyl]benzyl}}sulfamoylbenzoicacid,2-{N-[5-(4-chlorobenzenesulfonylamino)pentyl]-N-{3-[2(2-guinolyl)ethyl]benzyl}}sulfamoylbenzoicacid,2-{N-[4-(4-chlorobenzenesulfonylamino)butyl]-N-{3-[(2-guinolyl)methoxy]benzyl}}sulfamoylbenzoicacid,2-{N-[4-(4-chlorobenzenesulfonylamino)butyl]-N-{3-[(7-chloro-2-quinolyl)methoxy]benzyl}}sulfamoylbenzoicacid, 2-{N-[4-(4-chlorobenzenesulfonylamino)butyl]-N-{3-[2-(2-quinolyl)ethenyl]bensyl}}sulfamoylbenzoicacid, and 2-{N-[4-(4-chlorobenzenesulfonylamino)butyl]-N-{3-[(7-chloro-2-quinoyl)ethenyl]benzyl}}sulfamoylbenzoicacid.
 8. A sulfamoylbenzoic acid derivative or a pharmaceuticallyacceptable salt, hydrate or solvate thereof selected form the groupconsisting of2-{N-[4(4-chlorobenzenesulfonylamino)butyl]-N-{3-[(4-isopropyl-2-thiazolyl)metboxy]benzyl}}sulfamoylbenzoicacid,2-{N-[5-(4-chlorobenzenesulfonylamino)pentyl]-N-{3-[(4-isopropyl-2-thiazolyl)methoxy]benzyl}}sulfamoylbenzoicacid,2-{N-[4-(4-chlorobenzenesulfonylamino)butyl]-N-{3-[2-(4-cyclobutyl-2-thiazolyl)ethyl]benzyl}}sulfamoylbenzoicacid, and2-{N-[5-(4-chlorobenzenesulfonylamino)pentyl]-N-{3-[2-(7-chloro-2-quinolyl)ethyl]benzyl}}sulfamoylbenzoicacid, and2-{N-[5-(4-chlorobenzenesulfonylamino)pentyl]-N-{3-[2-(2-quinolyl)ehtyl]benzyl}}sulfamoylbenzoicacid.
 9. A benzylamine derivative represented by a general formula (II):

wherein R1 and R2 which may be the same or different, are hydrogenatoms, C₃₋₈ cycloalkyl groups, optionally substituted C₁₋₆ alkyl groups,optionally substituted aryl groups or form, together with the ring

a condensed ring represented by formula

which may be substituted with an optionally substituted C₁₋₆ alkylgroup, an amino acid group, a cyano group, a nitro group, a hydroxylgroup, a halogen atom or a C₁₋₅ alkoxy group, X is an oxygen atom, anitrogen atom, a sulfur atom or —CH═CH—, R3 is an optionally substitutedphenylsulfonylamino group, an optionally subtiiuted phenylsulfonyl groupor an optionally substituted phenylsulfoxide group, n is an integer offrom 2 to 6, A is —O—B—, —B—O—, —S—B—, —B—S— or —B—, and B is a C₁₋₆alkylene group or a C₂₋₅ alkenylene group, provided that the caseswherein R1 is a C₁₋₆ alkyl group, a C₃₋₈ cycloalkyl group or a phenylgroup, R2 is a hydrogen atom, A is a vinylene group, and X is a sulfuratom are excluded) or a pharmaceutically acceptable salt thereof.
 10. Apharmaceutical composition comprising as an active ingredient the2-sulfamoylbenzoic acid derivative according to claim 1 or apharnaceutically acceptable salt, hydrate or solvate thereof and apharmaceutically acceptable carrier.
 11. An anti-allergic agentcomprising as an active ingredient the 2-sulfamoylbenzoic acidderivative according to claim 1 or a pharmaceutically acccptable salt,hydrate or solvate thereof and a pharmaceutically acceptable carrier.12. A leucotriene and thromboxane A₂ antagonistic agent comprising as anactive ingredient the 2-sulfamoylbenzoic acid derivative according toclaim 1 or a pharmaceutically acceptable salt, hydrate or solvatethereof and a pharmaceutically acceptable carrier.
 13. Thepharmaceutical composition of claim 10 wherein the solvate is formed byusing a solution selected from the group consisting of acetone,2-butanol, 2-propanol, ethanol, ethyl acetate, tetrahydrofuran anddiethyl ether.
 14. The anti-allergic agent of claim 11 wherein thesolvate is formed by using a soluton selected from the group consistingof acetone, 2-butanol, 2-propanol, ethanol, ethyl acetate,tetrahydrofuran and diethyl ether.
 15. The leucotriene and thromboxaneA₂ antagonistic agent of claim 12 wherein the solvate is formed by usinga solution selected from the group consisting of acetone, 2-butanol,2-propanol, ethanol, ethyl acetate, tetrahydrofuran and diethyl ether.